46, XX disorder of sexual development associated with mixed germ cell tumor of the prostate: a rare case report.

BACKGROUND: Extragonadal germ cell tumors originating from the prostate are exceptionally rare. To the best of our knowledge, there have been no reported cases of mixed germ cell tumors in individuals with 46 XX disorder of sex development. In this study, we conducted a comprehensive analysis using whole genome sequencing to investigate the clinicopathological and molecular genetic characteristics of a submitted case, with the objective of elucidating its underlying pathogenesis. CASE PRESENTATION: A 40-year-old male patient was diagnosed with a combination of 46, XX disorder of sex development and a primary prostate mixed germ cell tumor with yolk sac tumor and teratoma components. Whole-genome sequencing revealed that the tumor cells had a high somatic mutational load. Analysis of genomic structural variations and copy number variants confirmed the patient's karyotype as 46, XX (SRY +). Additionally, the patient exhibited short stature, small bilateral testes, slightly enlarged breasts, elevated serum alpha-fetoprotein concentrations, elevated follicle-stimulating hormone and luteinizing hormone levels, and low testosterone levels. DISCUSSION: A case of 46, XX disorder of sex development, along with a primary prostatic mixed germ cell tumor, was diagnosed. This diagnosis has contributed to advancing our understanding of the genetic and phenotypic profile of the disease and may provide some insights for its treatment.

Enhanced Commendable Sensitivity and Specificity for MSI in Colorectal Cancer by a New PCR-HRM Based 8-Loci MSI Assay.

BACKGROUND: This study evaluated the performance of the PCR-HRM assay by comparing it with immunohistochemistry (IHC) for mismatch repair (MMR) proteins and the PCR capillary electrophoresis (PCR-CE) methods. RESULTS: A total of 224 patients with colorectal cancer participated in the study, with nearly half having mismatch repair deficiency (dMMR) tissues and the remainder possessing pMMR tissues. There was a 97.77% concordance between the PCR-HRM assay and IHC, and a 97.56% concordance between PCR-HRM and the PCR-CE assay. In comparison with IHC for dMMR proteins, the PCR-HRM demonstrated a sensitivity of 96.36% and a specificity of 99.12%. When juxtaposed with the PCR-CE assay, its sensitivity was 98.96% and specificity stood at 96.33%. The mutations observed in the microsatellite loci were uniformly distributed across all eight loci. Discrepant outcomes were more frequent in instances of MLH1 and PMS2 deficiency. Furthermore, the germline mutation status of MLH1, MSH2, PMS2, and MSH6 in 62 patients was ascertained using next-generation sequencing. All patients displaying MMR gene pathogenic mutations (N = 14) were identified as MSI-H by PCR-HRM, whereas those with MSS tissues (N = 43) did not exhibit MMR gene pathogenic mutations. Thus, the PCR-HRM method proficiently pinpoints tumors with verified germline MMR mutations, indicative of Lynch syndrome. CONCLUSION: Conclusively, the PCR-HRM assay emerges as a swift and congruent diagnostic tool for microsatellite instability, boasting commendable sensitivity and specificity in colorectal cancer.

JMJD5 cleaves monomethylated histone H3 N-tail under DNA damaging stress.

The histone H3 N-terminal protein domain (N-tail) is regulated by multiple posttranslational modifications, including methylation, acetylation, phosphorylation, and by proteolytic cleavage. However, the mechanism underlying H3 N-tail proteolytic cleavage is largely elusive. Here, we report that JMJD5, a Jumonji C (JmjC) domain-containing protein, is a Cathepsin L-type protease that mediates histone H3 N-tail proteolytic cleavage under stress conditions that cause a DNA damage response. JMJD5 clips the H3 N-tail at the carboxyl side of monomethyl-lysine (Kme1) residues. In vitro H3 peptide digestion reveals that JMJD5 exclusively cleaves Kme1 H3 peptides, while little or no cleavage effect of JMJD5 on dimethyl-lysine (Kme2), trimethyl-lysine (Kme3), or unmethyl-lysine (Kme0) H3 peptides is observed. Although H3 Kme1 peptides of K4, K9, K27, and K36 can all be cleaved by JMJD5 in vitro, K9 of H3 is the major cleavage site in vivo, and H3.3 is the major H3 target of JMJD5 cleavage. Cleavage is enhanced at gene promoters bound and repressed by JMJD5 suggesting a role for H3 N-tail cleavage in gene expression regulation.

Increased interleukin-22 levels in lupus nephritis and its associated with disease severity: a study in both patients and lupus-like mice model.

OBJECTIVES: Interleukin-22 (IL-22) has been considered as an inflammatory cytokine. In the present study, we investigated the potential role of IL-22 in lupus nephritis (LN). METHODS: We examined the IL-22 levels of serum and kidney tissue from LN patients and MRL/lpr mice. An intraperitoneal injection of saline, isotype control antibody (IgG), prednisone (3mg/kg/mouse), or anti-IL-22 mAb (5µg/kg/mouse or 25µg/kg/mouse) was administered twice a week from 6 to 18 weeks of age. RESULTS: IL-22 levels in both serum and kidney were significantly higher in LN patients as compared with those in healthy controls. The serum and renal levels of IL-22 in MRL/lpr mice were significantly increased over time. After MRL/lpr mice were treated with anti-IL-22 monoclonal antibody (mAb) for 12 weeks, significantly less urine protein and lower serum levels of creatinine and urea nitrogen were found. In addition, less renal injury score and few number of inflammatory cells per glomerulus were observed in MRL/lpr mice treated with anti-IL-22 mAb as compared with control groups. CONCLUSIONS: Our results suggest that IL-22 as a pathogenic cytokine might be a potential target for treatment of lupus nephritis.

Physical interaction between human ribonucleotide reductase large subunit and thioredoxin increases colorectal cancer malignancy.

Ribonucleotide reductase (RR) is the rate-limiting enzyme in DNA synthesis, catalyzing the reduction of ribonucleotides to deoxyribonucleotides. During each enzymatic turnover, reduction of the active site disulfide in the catalytic large subunit is performed by a pair of shuttle cysteine residues in its C-terminal tail. Thioredoxin (Trx) and glutaredoxin (Grx) are ubiquitous redox proteins, catalyzing thiol-disulfide exchange reactions. Here, immunohistochemical examination of clinical colorectal cancer (CRC) specimens revealed that human thioredoxin1 (hTrx1), but not human glutaredoxin1 (hGrx1), was up-regulated along with human RR large subunit (RRM1) in cancer tissues, and the expression levels of both proteins were correlated with cancer malignancy stage. Ectopically expressed hTrx1 significantly increased RR activity, DNA synthesis, and cell proliferation and migration. Importantly, inhibition of both hTrx1 and RRM1 produced a synergistic anticancer effect in CRC cells and xenograft mice. Furthermore, hTrx1 rather than hGrx1 was the efficient reductase for RRM1 regeneration. We also observed a direct protein-protein interaction between RRM1 and hTrx1 in CRC cells. Interestingly, besides the known two conserved cysteines, a third cysteine (Cys779) in the RRM1 C terminus was essential for RRM1 regeneration and binding to hTrx1, whereas both Cys32 and Cys35 in hTrx1 played a counterpart role. Our findings suggest that the up-regulated RRM1 and hTrx1 in CRC directly interact with each other and promote RR activity, resulting in enhanced DNA synthesis and cancer malignancy. We propose that the RRM1-hTrx1 interaction might be a novel potential therapeutic target for cancer treatment.

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma.

Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.

DFMG decreases angiogenesis to uphold plaque stability by inhibiting the TLR4/VEGF pathway in mice.

The aim of this study was to elucidate the specific mechanism through which 7-difluoromethoxy-5,4'-dimethoxygenistein (DFMG) inhibits angiogenesis in atherosclerosis (AS) plaques, given its previously observed but poorly understood inhibitory effects. In vitro, a model using Human Umbilical Vein Endothelial (HUVEC-12) cells simulated the initial lesion in the atherosclerotic pathological process, specifically oxidative stress injury, by exposing cells to 30 µmol/L LPC. Additionally, an AS mouse model was developed in ApoE knockout mice through a 16-week period of high-fat feeding. DFMG demonstrated a reduction in tubule quantities in the tube formation assay and neovascularization induced by oxidative stress-damaged endothelial cells in the chicken embryo chorioallantoic membrane assay. Furthermore, DFMG decreased lipid levels in the blood of ApoE knockout mice with AS, along with a decrease in atherosclerotic plaques and neovascularizations in the aortic arch and descending aorta of AS animal models. DFMG treatment upregulated microRNA140 (miR-140) expression and suppressed VEGF secretion in HUVEC-12 cells. These effects were counteracted by Toll-like receptor 4 (TLR4) overexpression in HUVEC-12 cells subjected to oxidative injury or in a mouse model of AS. Dual-luciferase reporter assays demonstrated that miR-140 directly targeted TLR4. Immunohistochemical assay findings indicated a significant inverse relationship between miR-140 expression and TLR4 expression in ApoE knockout mice subjected to a high-fat diet. The study observed a close association between DFMG inhibitory effects on angiogenesis and plaque stability in AS, and the inhibition of the TLR4/NF-κB/VEGF signaling pathway, negatively regulated by miR-140.

Concordance of Abundance for Mutational EGFR and Co-Mutational TP53 with Efficacy of EGFR-TKI Treatment in Metastatic Patients with Non-Small-Cell Lung Cancer.

The present study aimed to investigate the influence of the mutation abundance of the epidermal growth factor receptor (EGFR) and its co-mutation with TP53 on the therapeutic efficacy of tyrosine kinase inhibitor (TKI) treatment in patients with metastatic lung adenocarcinoma (LUAD). In total, 130 patients (January 2018-September 2022) with metastatic LUAD from the Second Affiliated Hospital of Zhejiang University were included. Kaplan-Meier analysis was performed to measure the duration of drug application (DDA) and the log-rank test was used to compare differences. Univariate and multivariate analyses of Cox proportional hazard regression models were used to evaluate the association between the relevant clinicopathological factors and DDA. Hazard ratios with 95% confidence intervals were also calculated. Among the 130 patients who were treated with first-generation EGFR-TKIs, 86 showed high-EGFR mutation abundance (>22.0%) and 44 showed low-EGFR mutation abundance (≤22.0%). Patients in the high-EGFR group had a greater DDA than those in the low-EGFR group (p < 0.05). The results of the subgroup analysis were consistent with those of the total mutation population (exon19: >18.5% vs. ≤18.5%, 14 months vs. 10 months, p = 0.049; exon21: >22.0% vs. ≤22.0%, 15 months vs. 9 months, p = 0.005). In addition, the mutation abundance of TP53 was negatively correlated with the DDA (p < 0.05). Patients in the combination group had a better DDA than those in the monotherapy group (p < 0.05). Subgroup analysis showed that, among the low mutation abundance of the EGFR exon 21 or 19 cohort, the combination group had a better DDA than the monotherapy group (p < 0.05). An EGFR mutation abundance greater than 22.0% was a positive predictor of DDA in patients with metastatic LUAD. However, a TP53 mutation abundance higher than 32.5% could reverse this situation. Finally, first-line treatment with EGFR-TKIs plus chemotherapy is a potential treatment strategy for patients with low-abundance EGFR mutations.

JMJD5 inhibits lung cancer progression by facilitating EGFR proteasomal degradation.

Aberrant activation of epidermal growth factor receptor (EGFR) signaling is closely related to the development of non-small cell lung cancer (NSCLC). However, targeted EGFR therapeutics such as tyrosine kinase inhibitors (TKIs) face the challenge of EGFR mutation-mediated resistance. Here, we showed that the reduced JmjC domain-containing 5 (JMJD5) expression is negatively associated with EGFR stability and NSCLC progression. Mechanically, JMJD5 cooperated with E3 ligase HUWE1 to destabilize EGFR and EGFR TKI-resistant mutants for proteasomal degradation, thereby inhibiting NSCLC growth and promoting TKI sensitivity. Furthermore, we identified that JMJD5 can be transported into recipient cells via extracellular vesicles, thereby inhibiting the growth of NSCLC. Together, our findings demonstrate the tumor-suppressive role of JMJD5 in NSCLC and suggest a putative therapeutic strategy for EGFR-related NSCLC by targeting JMJD5 to destabilize EGFR.

Clinical, Morphological, and Molecular Study on Grade 2 and 3 Pleomorphic Xanthoastrocytoma.

PURPOSE: Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm2). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs. METHODS: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). RESULTS: Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01). CONCLUSION: These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA.

E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma.

Ribonucleotide reductase (RR) is a rate-limiting enzyme that facilitates DNA replication and repair by reducing nucleotide diphosphates (NDPs) to deoxyribonucleotide diphosphates (dNDPs) and is thereby crucial for cell proliferation and cancer development. The E2F family of transcription factors includes key regulators of gene expression involved in cell cycle control. In this study, E2F8 expression was significantly increased in most cancer tissues of lung adenocarcinoma (LUAD) patients and was correlated with the expression of RRM2 through database and clinical samples analysis. The protein expression of E2F8 and RRM2 were positively correlated with tumor-node-metastasis (TNM) pathological stage, and high expression of E2F8 and RRM2 predicted a low 5-year overall survival rate in LUAD patients. Overexpression and knockdown experiments showed that E2F8 was essential for LUAD cell proliferation, DNA synthesis, and cell cycle progression, which were RRM2-dependent. Reporter gene, ChIP-qPCR, and DNA pulldown-Western blot assays indicated that E2F8 activated the transcription of the RRM2 gene by directly binding with the RRM2 promoter in LUAD cells. Previous studies indicated that inhibition of WEE1 kinase can suppress the phosphorylation of CDK1/2 and promote the degradation of RRM2. We further showed here that the combination of E2F8 knockdown with MK-1775, an inhibitor of WEE1 being evaluated in clinical trials, synergistically suppressed proliferation and promoted apoptosis of LUAD cells in vitro and in vivo. Thus, this study reveals a novel role of E2F8 as a proto-oncogenic transcription activator by activating RRM2 expression in LUAD, and targeting both the transcription and degradation mechanisms of RRM2 could produce a synergistic inhibitory effect for LUAD treatment in addition to conventional inhibition of RR enzyme activity.

Decreased Tertiary Lymphoid Structures in Lung Adenocarcinomas with ALK Rearrangements.

PURPOSE: This study sought to characterize the tumor immune microenvironment (TIME) of lung adenocarcinomas with ALK rearrangements (ALK+ LUAD), which responds poorly to immune checkpoint inhibitors (ICIs) therapy. MATERIALS AND METHODS: Immune score evaluation and immunohistochemical (IHC) validation of B cells, cytotoxic, helper, regulatory T cells, dendritic cells, and tumor-associated macrophages were performed on the TCGA cohort and the whole tissue sections of our matched surgical samples, respectively, between ALK+ and ALK- LUAD. The formation and spatial organization of TLS, intra- and extra-TLS immune cell features, and tumor PD-L1 expression were analyzed independently. RESULTS: Immune scores and TLS-signature gene levels were found to be lower in ALK+ TCGA LUAD. Quantitative IHC comparison confirmed the lower densities of TLS (0.10/mm2 vs. 0.34/mm2, p = 0.026) and intra-TLS immune cells (CD4+ helper T cells: 57.65/mm2 vs. 274.82/mm2, p = 0.026; CD8+ cytotoxic T cells: 22.46/mm2 vs. 172.83/mm2, p = 0.018; and CD20+ B cells: 36.08/mm2 vs. 207.29/mm2, p = 0.012) in ALK+ surgical samples. The TLS formation was negatively correlated with tumor progression in ALK+ tumors. The proportion of intra-TLS CD8+ cytotoxic T cells was the independent protective factors of node metastasis (HR: 0.599, 95% CI: 0.414-0.868, p = 0.007), and the density of intra-TLS CD20+ B cells was the independent protective factor of pStage (HR: 0.641, 95% CI: 0.446-0.922, p = 0.016). Tumors with intratumoral TLS showed significantly higher expression of PD-L1 (p = 0.029). CONCLUSION: ALK+ LUAD harbored a cold TIME featured by decreased TLS formation, which closely correlated to tumor progression and might contribute to the poor efficiency of ICIs.

Super-enhancers and novel therapeutic targets in colorectal cancer.

Transcription factors, cofactors, chromatin regulators, and transcription apparatuses interact with transcriptional regulatory elements, including promoters, enhancers, and super-enhancers (SEs), to coordinately regulate the transcription of target genes and thereby control cell behaviors. Among these transcriptional regulatory components and related elements, SEs often play a central role in determining cell identity and tumor initiation and progression. Therefore, oncogenic SEs, which are generated within cancer cells in oncogenes and other genes important in tumor pathogenesis, have emerged as attractive targets for novel cancer therapeutic strategies in recent years. Herein, we review the identification, formation and activation modes, and regulatory mechanisms for downstream genes and pathways of oncogenic SEs. We also review the therapeutic strategies and compounds targeting oncogenic SEs in colorectal cancer and other malignancies.

O6-methylguanine DNA methyltransferase is upregulated in malignant transformation of gastric epithelial cells via its gene promoter DNA hypomethylation.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a suicide enzyme that repairs the mispairing base O6-methyl-guanine induced by environmental and experimental carcinogens. It can transfer the alkyl group to a cysteine residue in its active site and became inactive. The chemical carcinogen N-nitroso compounds (NOCs) can directly bind to the DNA and induce the O6-methylguanine adducts, which is an important cause of gene mutation and tumorigenesis. However, the underlying regulatory mechanism of MGMT involved in NOCs-induced tumorigenesis, especially in the initiation phase, remains largely unclear. AIM: To investigate the molecular regulatory mechanism of MGMT in NOCs-induced gastric cell malignant transformation and tumorigenesis. METHODS: We established a gastric epithelial cell malignant transformation model induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methyl-N-nitroso-urea (MNU) treatment. Cell proliferation, colony formation, soft agar, cell migration, and xenograft assays were used to verify the malignant phenotype. By using quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis, we detected the MGMT expression in malignant transformed cells. We also confirmed the MGMT expression in early stage gastric tumor tissues by qPCR and immunohistochemistry. MGMT gene promoter DNA methylation level was analyzed by methylation-specific PCR and bisulfite sequencing PCR. The role of MGMT in cell malignant transformation was analyzed by colony formation and soft agar assays. RESULTS: We observed a constant increase in MGMT mRNA and protein expression in gastric epithelial cell malignant transformation induced by MNNG or MNU treatment. Moreover, we found a reduction of MGMT gene promoter methylation level by methylation-specific PCR and bisulfite sequencing PCR in MNNG/MNU-treated cells. Inhibition of the MGMT expression by O6-benzylguanine promoted the MNNG/MNU-induced malignant phenotypes. Overexpression of MGMT partially reversed the cell malignant transformation process induced by MNNG/MNU. Clinical gastric tissue analysis showed that MGMT was upregulated in the precancerous lesions and metaplasia tissues, but downregulated in the gastric cancer tissues. CONCLUSION: Our finding indicated that MGMT upregulation is induced via its DNA promoter hypomethylation. The highly expressed MGMT prevents the NOCs-induced cell malignant transformation and tumorigenesis, which suggests a potential novel approach for chemical carcinogenesis intervention by regulating aberrant epigenetic mechanisms.

pH-responsive magnetic artificial melanin with tunable aggregation-induced stronger magnetism for rapid remediation of plastic fragments.

The global occurrence of plastic fragment pollutants in water resources has raised concerns about food safety, drinking water security, and long-term ecological impacts worldwide. The different chemical nature, the persistence, and the smaller size make micro-plastics accumulators for toxins that pose a potential threat to human health. Generally, the smaller the size of the plastic fragments is, the more difficult it is to remove them from the aquatic environment. Methods to remove plastics from water or other media are highly needed. Here, we develop core-shell superparamagnetic melanin nanoparticles, which can put magnetism on nano-/micro-plastics within 30 s and then rapidly remove them from water by applying an external magnetic field. The shell material (artificial nano-melanin) provides simultaneously attractive electrostatic, hydrophobic interaction, and van der Waals' forces to attract nano-/micro-plastics, which plays a key role in the rapid remediation of the plastic fragments. With this principle applied to a simple method, the average removal efficiency achieves 89.3%. We show a method for high-throughput remediation of various micro-plastics with simple materials and processes, which have the potential for rapid, green, and large-scale remediation in the future.

High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer.

BACKGROUND: The monocarboxylate transporter (MCT) family especially MCT1 and MCT4 have been recognized to play an important role in lactate transport, a key glycolytic product. The expression of MCT1 and MCT4 expression was previously found to be related to poor outcome in various cancer types. In this study, we investigated the expression status of MCT1 and MCT4 and their relationship with prognosis in non-small cell lung cancer (NSCLC). METHODS: Expression of MCT4 and MCT1 in NSCLC tumor and adjacent lung tissues were detected by immunohistochemistry. Kaplan-Meier plots were used to evaluate two proteins' prognostic role, and the log-rank test obtained the P value. For multivariate analysis, the Cox proportional-hazards regression method was performed. RESULTS: High MCT4 and MCT1 expression was observed in cancer cells, with a rate of 45% for MCT4 versus 15% for MCT1 among all NSCLC patients. High expression of MCT4, and not MCT1, was associated with worse overall survival (OS) [hazard ratio (HR) =1.96 (1.06-3.75), P=0.032] and progression-free survival (PFS) [HR =1.72 (1.05-2.93), P=0.032] in NSCLC patients. In our multivariate analysis, advanced cancer stage and high MCT4 level were identified as independent predictive indicators for both PFS [HR(MCT4) =1.888 (1.114-3.199), P=0.018 and OS [HR (MCT4) =2.421 (1.271-4.610), P=0.007]. Subgroup and interaction analyses were also performed in different clinical characteristic groups and no significant differences were observed. CONCLUSIONS: High MCT4 expression is a predictive marker for worse outcome in NSCLC patients.

Regenerative field effect transistor biosensor for in vivo monitoring of dopamine in fish brains.

The detection of dopamine, one of the neurotransmitters in cerebral physiology, is critical in studying brain activities and understanding brain functions. However, regenerative biosensor for monitoring dopamine in the progress of physiological and pathological events is still challenging, due to lack of the platform for repetitive on-line detection-regeneration cycle. Herein, we have developed a regenerated field effect transistor (FET) combined with in vivo monitoring system. In this biosensor, gold-coated magnetic nanoparticles (Fe3O4@AuNPs) acts as a regenerated recognition unit for dopamine. Just by simple removal of a permanent magnet, dopamine on the biosensor interface are catalyzed by tyrosinase, thus achieving the regeneration of the biosensor. As a result, this FET biosensor not only reveals high sensitivity and selectivity, but also exhibits excellent stability after 15 regeneration processing. This biosensor is capable of monitor dopamine with a linear range between 1 µmol L-1 and 120 µmol L-1 and low detection limit (DL) of 3.3 nmol L-1. Then, the platform has been successfully applied in dopamine analysis in fish brain under global cerebral cortical neurons. This FET biosensor is the first to on-line and remote control the sensitivity and DL by permanent magnet. It opens the door to reusable, inexpensive and large-scale productions.

A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer.

Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.

Metastasis of Sarcomatoid Malignant Mesothelioma With p16/CDKN2A Deletion Manifested as a Subcutaneous Mass in the Back: A Case Report and Review of Literature.

Sarcomatoid malignant mesothelioma (MM) is a rare and aggressive disease, and its diagnosis is challenging. A 60-year-old man presented with a recurrent subcutaneous mass in his right back after the initial resection. A chest computed tomography (CT) scan found right pleural thickening, nodular pleural thickening, pleural effusion, mediastinal, and right infraclavicular lymph nodes enlargement, which indicated a right pleura MM. Immunohistochemical stains of the resected mass showed sarcomatous atypical spindle cells, which were positive for pan-CKs (clone Anti-cytokeratin cocktail AE1/AE3), cytokeratin 5/6 (CK5/6), Wilm's tumor 1, podoplanin, vimentin and programmed death-ligand 1 (PD-L1), and negative for Napsin A, thyroid transcription factor 1, CDX 2, calretinin and desmin, and fluorescent in situ hybridization detected homozygous p16/cyclin-dependent kinase inhibitor 2A (p16/CDKN2A) deletion. The association of the chest CT features and the pathological assessment confirmed metastatic MM in the subcutaneous layer of the back. Moreover, positron emission tomography-CT showed multiple metastases in his brain. He developed massive right pleural effusion and chest tightness soon, and the mass kept growing despite local and systemic treatments. The patient die of pulmonary failure in 3 months.

Comparison of the clinicopathological features of pancreatic solid pseudopapillary neoplasms between males and females: gender does matter.

BACKGROUND: Solid pseudopapillary neoplasms (SPN) of the pancreas are a rare and low-grade malignant entity with a female predominance. However, it also occurs in males, but the rarity and lack of concern makes its clinicopathological features unclarified. METHODS: The morphological, immunohistochemical, prognostic features and CTNNB1 exon 3 mutation status of SPN were compared semi-quantitively between 9 male and 21 female patients. RESULTS: SPN in males grew in a distinctive solid pattern, with abundant fibrotic stroma and clear cells. Collagen tended to be the main component of tumor stroma in males, while hyaluronan composed a considerable proportion in females. A much stronger expression of androgen receptor (AR) was found in males, and CD56 and/or synaptophysin (Syn) was expressed frequently in both genders. All patients survived. One male patient had post-operational liver nodules and accepted interventional therapy without biopsy. Mutations of CTNNB1 exon 3 were observed in all cases, distributed at codon 32, 33 and 37 in both genders, as well as 34, 41 and 62 in females. CONCLUSION: SPN in males presented with significantly different morphological features from that in females, which might be helpful in differential diagnosis, especially when with extensive positivity for CD56 and/or Syn. The stronger expression of AR in males might be a clue to explore the underlying mechanism of the gender difference.