Recent progress of ferroptosis in cancers and drug discovery.

Ferroptosis is a nonapoptotic form of cell death characterized by iron dependence and lipid peroxidation. Ferroptosis is involved in a range of pathological processes, such as cancer. Many studies have confirmed that ferroptosis plays an essential role in inhibiting cancer cell proliferation. In addition, a series of small-molecule compounds have been developed, including erastin, RSL3, and FIN56, which can be used as ferroptosis inducers. The combination of ferroptosis inducers with anticancer drugs can produce a significant synergistic effect in cancer treatment, and patients treated with these combinations exhibit a better prognosis than patients receiving traditional therapy. Therefore, a thorough understanding of the roles of ferroptosis in cancer is of great significance for the treatment of cancer. This review mainly elaborates the molecular biological characteristics and mechanism of ferroptosis, summarizes the function of ferroptosis in cancer development and treatment,illustrates the application of ferroptosis in patient's prognosis prediction and drug discovery, and discusses the prospects of targeting ferroptosis.

Analyzing the correlation between low proportion of hobnail features in papillary thyroid carcinoma and clinical aggressiveness risk.

PURPOSE: Hobnail features may enhance the clinical aggressiveness of papillary thyroid carcinoma (PTC). However, whether a low proportion (<30%) of these features contributes to increased PTC aggressiveness remains unclear. This study investigated whether PTC cases with a low proportion hobnail features (<30%) exhibit clinical invasiveness and pathological features of aggressiveness. METHODS: Pathological specimens from patients with postoperatively diagnosed PTC were retrospectively analyzed. Among them, 29 PTC cases with a low proportion of hobnail features (<30%) were compared with 173 consecutive classical PTC (cPTC) cases. Data regarding age at presentation, sex, tumor size, number of tumors, and histological characteristics were obtained by reviewing electronic medical records. Postoperative information was obtained during follow-up visits and telephone interviews. RESULTS: Twenty-nine patients with PTC with a low proportion of hobnail features (<30%) were identified, exhibiting a median age of 34 years. At a median follow-up of 31 (IQR, 23-37) months, two patients had recurrent disease in the PTC with a low proportion of hobnail features (<30%) group, whereas there was no recurrence in the cPTC group. No distant metastasis and postoperative mortality were observed in either group. Compared with the cPTC group, patients with PTC and a low proportion of hobnail features exhibited larger tumor volumes and higher susceptibility to capsular invasion and lymph node metastasis. Tumor size and hobnail features emerged as independent risk factors for lymph node metastasis. CONCLUSION: PTC with a low proportion hobnail features (<30%) and larger tumor volumes are associated with the occurrence of lymph node metastasis. A low proportion of hobnail features (<30%) in PTC may heighten invasiveness, elevating the risk of recurrence.

TyG-GGT is a Reliable Non-Invasive Predictor of Advanced Liver Fibrosis in Overweight or Obese Individuals.

BACKGROUND: Liver fibrosis is a predisposing factor for liver cancer. This study will investigate the predictive role of the Triglyceride-glucose and Gamma-glutamyl transferase index (TyG-GGT) as a non-invasive indicator of advanced liver fibrosis in individuals with obesity or overweight. METHOD: We enrolled patients who underwent metabolic and bariatric surgery as well as intraoperative liver biopsies at Zhejiang provincial people's hospital from August 2020 to March 2023. Clinical characteristics, comorbidities, laboratory data, and pathological variables of patients were collected and analysed. Then, we conducted logistics regression model to compare the performance of the TyG-GGT index with other 4 non-invasive models. RESULTS: A total of 65 patients were included in this study. 43(66.2%) of them were female, with the mean body mass index (BMI) of 39.0 ± 7.3 kg/m2. Meanwhile, 24(36.9%) patients were diagnosed with diabetes. Advanced liver fibrosis were observed in 16.9% of patients, while liver cirrhosis was found in 4.6% of patients. The multivariable logistics regression showed that TyG-GGT was an independent risk factor of advanced liver fibrosis (OR = 6.989, P = 0.049). Additionally, compared to another 4 non-invasive liver fibrosis models (NFS = 0.66, FIB4 = 0.65, METS-IR = 0.68, APRI = 0.65), TyG-GGT exhibits the highest AUC value of 0.75. CONCLUSIONS: More than one-third of patients undergoing metabolic and bariatric surgery are afflicted with nonalcoholic steatohepatitis (NASH), and a significant proportion exhibit advanced fibrosis. TyG-GGT was a potentially reliable predictor for screening individuals with overweight or obesity at high risk of advanced liver fibrosis, thus providing clinical guidance for early intervention in this targeted group.

Concordance between microsatellite instability and mismatch repair protein expression in colorectal cancer and their clinicopathological characteristics: a retrospective analysis of 502 cases.

Microsatellite instability (MSI) is one of the hallmarks of colorectal cancer (CRC). Mismatch repair (MMR) protein expression may reflect MSI status. To analyze the concordance between MSI and MMR expression in CRC and their clinicopathological characteristics, 502 CRC patients were retrospectively collected in this study. Polymerase chain reaction-capillary electrophoresis (PCR-CE) was used to measure MSI, and MMR expression was determined by immunohistochemistry (IHC). The causes of non-concordance were analyzed. Chi-square test was used to find the correlation between MSI and various clinicopathological parameters. PCR-CE results showed 64 (12.7%) patients had high microsatellite instability (MSI-H); low microsatellite instability (MSI-L) and microsatellite stable (MSS) cases were 19 (3.8%)and 419 (83.5%), respectively. With regard to IHC, 430 (85.7%) showed proficient mismatch repair (pMMR) and 72 (14.3%) showed deficient mismatch repair (dMMR). The coincidence rate of MSI and MMR expression in CRC was 98.4% (494/502), with good concordance (Kappa = 0.932). Using PCR-CE as the gold standard, the sensitivity, specificity, positive predictive value, and negative predictive value of IHC were 100%, 98.2%, 88.9%, and 100%, respectively. MSI-H was more common in women, right colon, tumors ≥ 5 cm, ulcerative type, mucinous adenocarcinoma, poor differentiation, T stage I/II, and without lymph node or distant metastasis for CRC patients. In summary, MSI exhibited some typical clinicopathological characteristics. MSI and MMR expression in CRC had good concordance. However, it is still extremely necessary to perform PCR-CE. We recommend that testing packages of different sizes should be developed in clinical practice to create a testing echelon, to facilitate comprehensive selection according to experimental conditions, clinical diagnosis, and treatment needs.

Papain exerts an anti-atherosclerosis effect with suppressed MPA-mediated foam cell formation by regulating the MAPK and PI3K/Akt-NF-κB pathways.

BACKGROUND: Papain possesses a potential anti-atherosclerosis (AS) effect. This study aimed to explore the inhibitory effects of papain on the monocyte-platelet aggregates (MPAs)-mediated production of foam cells in vitro and AS in vivo. RESEARCH DESIGN AND METHODS: THP-1 cells were treated by platelet, papain, nuclear factor-κB (NF-κB) inhibitor or activator. An AS rat model was treated with papain. The THP-1 cells, macrophages, and foam cells were detected, and CD36, CD11b and CCR2 (macrophages) and CD14 and CD41 (MPAs) were measured. The levels of inflammatory factors, lipoprotein, and MAPK and PI3K/Akt -NF-κB pathways proteins were determined. Finally, injury of the thoracic aorta of AS rats was observed. RESULTS: Papain reduced macrophage production, lipid accumulation, and foam cell formation in vitro and downregulated the expression of monocyte chemoattractant protein 1 (MCP-1), prostaglandin E2 (PGE2), and cyclooxygenase 2 (COX2), and that of p38, JNK, Akt, and p65. Moreover, NF-κB activator could reversed the inhibitory effects of papain. Similarly, papain alleviated aortic smooth muscle hyperplasia, lipid droplet accumulation, and collagen diffusion and inhibited the expression of inflammatory factors and p38, JNK, Akt, and p65 in vivo. CONCLUSIONS: Papain inhibited MPA-induced foam cell formation by inactivating the MAPK and PI3K/Akt-NF-κB pathways, thereby exerting an anti-AS effect.

Recurrent PRDM10 Fusions in Superficial CD34-Positive Fibroblastic Tumors : A Clinicopathologic and Molecular Study of 10 Additional Cases of an Emerging Novel Entity.

OBJECTIVES: Superficial CD34-positive fibroblastic tumor (SCD34FT) is a rare mesenchymal neoplasm. The genetic alterations of SCD34FT have yet to be determined. Recent studies suggest it overlaps with PRDM10-rearranged soft tissue tumor (PRDM10-STT). METHODS: This study aimed to characterize a series of 10 cases of SCD34FT using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS). RESULTS: The study recruited 7 men and 3 women aged between 26 and 64 years. The tumors were located in the superficial soft tissues of the thigh (8 cases), foot, and back (1 case each), ranging in size from 1.5 to 7 cm. The tumors were composed of sheets and fascicles of plump spindled to polygonal cells, with glassy cytoplasm and pleomorphic nuclei. Mitotic activity was absent or low. Common and uncommon stromal findings included foamy histiocytic infiltrates, myxoid changes, peripheral lymphoid aggregates, large ectatic vessels, arborizing capillary vasculature, and hemosiderin deposition. All tumors expressed CD34, and 4 demonstrated focal cytokeratin immunoexpression. In 7 of 9 (77.8%) cases analyzed, FISH identified PRDM10 rearrangement. Targeted NGS revealed a MED12::PRDM10 fusion in 4 of 7 cases tested. Follow-up showed no recurrence or metastasis. CONCLUSIONS: We demonstrate recurrent PRDM10 rearrangements in SCD34FT and provide additional evidence of a close relationship to PRDM10-STT.

Uterine Tumor Resembling Ovarian Sex Cord Tumor With Aggressive Histologic Features Harboring a GREB1-NCOA2 Fusion: Case Report With a Brief Review.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain lineage, that shows predominantly sex cord-like differentiation with a broad range of histologic appearances and polyphenotypic immunohistochemical features. Although generally having a favorable prognosis, a subset can recur/metastasize. Most recently, several studies of UTROSCT have described novel fusion genes involving ESR1 and GREB1 as the 5 partner, and NCOA1-3 as the 3 partner. Genotype and phenotype correlation has suggested that GREB1 -rearranged tumors may have a higher tendency to behave aggressively. Herein, we report a UTROSCT with aggressive histologic features harboring a GREB1-NCOA2 fusion. A 51-yr-old woman presented with menometrorrhagia and progressive dysmenorrhea and was found to have a submucous uterine lesion by ultrasonography. Gross examination of the hysterectomy specimen showed an 8.5-cm, polypoid, soft, intracavitary mass. Histologic examination revealed a deeply invasive neoplasm composed of uniform round to plump spindle cells, arranged predominantly in diffuse sheets and fascicles and focally in anastomosing cords patterns. Groups of rhabdoid tumor cells were occasionally noted. Worrisome features, including increased mitotic figures (up to 3/10 high power fields), geographic necrosis, and lymphovascular invasion, were evident. Immunohistochemical analysis showed variable positivity for epithelial, smooth muscle, neuroendocrine, and sex cord markers, as well as hormone receptors. RNA sequencing revealed an in-frame fusion between exon 3 of GREB1 and exon 14 of NCOA2 . Fluorescence in situ hybridization analyses confirmed rearrangements of both the GREB1 and NCOA2 loci. Our case lends further supports that GREB1 -rearranged UTROSCTs frequently exhibit aggressive histological features with inconspicuous sex cord-like differentiation.

Recurrent RET fusions in fibrosarcoma-like neoplasms in adult viscera: expanding the clinicopathological and genetic spectrum.

AIMS: RET-fused mesenchymal neoplasms mostly affect the soft tissue of paediatric patients. Given their responsiveness to selective RET inhibitors, it remains critical to identify those extraordinary cases occurring in the visceral organs of adults. In this study, we report three RET-rearranged spindle-cell tumours occurring in the visceral organs of adults. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted next-generation sequencing on clinically validated platforms were performed. The patients were 18, 53, and 55 years old and included one male and two females. The tumours were located in the kidney (case 1), small intestine (case 2), and ureter (case 3), with maximum diameters of 14, 5, and 1 cm, respectively. Histologically, all tumours displayed a morphological spectrum typical of fibrosarcoma, including moderately to highly cellular, nonpleomorphic, ovoid to spindle-shaped cells arranged in long fascicles or haphazardly within collagenised to myxohyaline stroma. Foci of irregular alveolar oedema-like structures and areas with microcystic and reticular arrangements were identified in the renal tumour. Staghorn-type vessels and foci of band-like stromal hyalinisation were observed in the small intestine tumour. Cases 1 and 2 were high-grade and pursed a highly aggressive clinical course, while case 3 was of intermediate grade with no tumour recurrence or metastasis 14 years after surgery. All three tumours expressed CD34, which was coexpressed with S100 protein in cases 2 and 3. Molecular genetic testing revealed PRKAR1A::RET, KIF5B::RET, and SPECC1L::RET in-frame gene fusions. CONCLUSION: Our study expands the clinicopathological and genetic spectrum of mesenchymal neoplasms associated with RET fusions.

ZNF521 Is Correlated with Tumor Immune Cell Infiltration and Act as a Valuable Prognostic Biomarker in Gastric Cancer.

Aim: To explore the correlations between the expression of zinc finger protein 521 (ZNF521) with immune invasion and prognosis of gastric cancer. Methods: Expression of ZNF521 was examined by immunohistochemistry in gastric cancer cases. Kaplan-Meier plotter was used to determine the relationships between ZNF521 and prognosis. TIMER and GEPIA were used to analyze the correlation between ZNF521 expression and gene markers of immune cell infiltration. Results: The expression of ZNF521 was up-regulated in gastric cancer samples. Kaplan-Meier analysis indicated that higher expression of ZNF521 was associated with poor prognosis. The expression of ZNF521 was correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells in gastric cancer, which also correlated with diverse immune marker sets. Conclusions: ZNF521 is correlated significantly with immune cell infiltration and is a valuable biomarker for prognosis in gastric cancer.

Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described, rare renal tumor that differs clinically, morphologically, and molecularly from papillary renal cell carcinoma (RCC). To further characterize the pathological spectrum of this rare tumor, in this study, we retrospectively identified 16 cases of PRNRP from three institutions to comprehensively investigate the clinicopathological and molecular genetic features, using immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and targeted next-generation sequencing (NGS). The patients included nine men and seven women, with age ranging from 47 to 80 years (median = 67.5 years, mean = 65 years). The tumor size ranged from 0.4 to 9.5 cm in the greatest dimension (median = 1.8 cm, mean = 2.6 cm). Most tumors (12/16) were incidentally identified by imaging studies. By AJCC stage, 15 were categorized as pT1 and 1 was pT2. Follow-up showed no recurrences, metastases, or disease-related deaths in all the 16 patients. Grossly, 14 cases demonstrated at least a partially cystic appearance. Microscopically, all PRNRPs except 1 (case 13) were composed predominantly of thin, branching papillary architecture covered by a single layer of cuboidal cells with finely granular cytoplasm, and low-grade nuclei typically located toward the apical surface away from the basement. Case 13 consisted mostly of solid, densely packed tubules with only a minor papillary component (5%). Other commonly seen histological features included hyalinized or edematous papillae (n = 11), lymphocyte aggregation in fibrovascular cores (n = 10), mast cell infiltration (n = 8), and intralesional hemorrhage (n = 7). Uncommonly seen histological features included lymphoid cuff (n = 4), hemosiderin deposition (n = 5), foci of clear cell change (n = 4), intracytoplasmic vacuoles (n = 4), eosinophilic hobnail cells (n = 2), and infarct-type necrosis (n = 1). Two PRNRPs were concurrent with ipsilateral clear cell papillary RCC and clear cell RCC, respectively. By IHC, the tumors were consistently positive for GATA3, CK7, and PAX8. Fourteen out of 16 tumors showed a basolateral-membranous E-cadherin expression pattern, and 12/16 cases were positive for 34ßE12.The expression of AMACR, CD10, and vimentin was either absent or only weak and focal. By targeted NGS, 13/14 evaluated PRNRPs harbored KRAS missense mutations involving c.35G>T resulting in p.G12V (7/13), c.35G>A resulting in p.G12D (4/13), and c.34G>T resulting in p.G12C (2/13). By FISH, 1/15 had gains of chromosomes 7 and 17, and 2/8 male cases had deletion of chromosomes Y. In conclusion, our study confirms that PRNRP is an indolent renal cell neoplasm with unique morphology, consistent immunohistochemical profile, and recurrent KRAS mutation. Our study expands the morphologic spectrum of PRNRP and provides further evidence supporting it as a novel entity.

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma.

BACKGROUND: Fibrinogen-like-protein 1 (FGL1), a member of the fibrinogen-related protein (FREP) family, is a major ligand of the immune inhibitory receptor lymphocyte-activation gene 3 (LAG-3). While FGL1 is strongly implicated in the development and prognosis of a variety of diseases, its role in hepatocellular carcinoma (HCC) is still disputed. Therefore, the role of FGL1 expression in the progression and prognosis of HCC was investigated. METHODS AND RESULTS: In the present study, bioinformatics analysis was first used to probe the expression profile of FGL1 in multiple malignant tumor tissues and paired normal tissues, and to explore the possible relationship between FGL1 and prognosis of HCC patients. Thereafter, the expression levels of FGL1 were determined and compared in human HCC cell lines, HCC tissues, peri-tumor tissues and normal liver tissues by western blot analysis. Furthermore, tissue microarrays were used to detect the expression of FGL1 through immunohistochemical staining and to verify whether the FGL1 expression level was associated with clinicopathological features and the prognosis of HCC patients. The results showed that FGL1 was downregulated significantly in most of the HCC cells lines and HCC tissues, corresponding to the results of the bioinformatics and western blot analyses. FGL1 expression level in HCC was found to be correlated to Edmondson grade and metastasis of the HCC. Additionally, high FGL1 expression was associated with better overall survival in HCC patients, suggesting that FGL1 could function as a tumor suppressor. CONCLUSIONS: The expression level of FGL1 can be correlated with the progression and prognosis of HCC, suggesting its potential as a prognostic biomarker.

Mouse Models of Hepatocellular Carcinoma: Classification, Advancement, and Application.

Hepatocellular carcinoma (HCC) is the subtype of liver cancer with the highest incidence, which is a heterogeneous malignancy with increasing incidence rate and high mortality. For ethical reasons, it is essential to validate medical clinical trials for HCC in animal models before further consideration on humans. Therefore, appropriate models for the study of the pathogenesis of the disease and related treatment methods are necessary. For tumor research, mouse models are the most commonly used and effective in vivo model, which is closer to the real-life environment, and the repeated experiments performed on it are closer to the real situation. Several mouse models of HCC have been developed with different mouse strains, cell lines, tumor sites, and tumor formation methods. In this review, we mainly introduce some mouse HCC models, including induced model, gene-edited model, HCC transplantation model, and other mouse HCC models, and discuss how to choose the appropriate model according to the purpose of the experiments.

Development of Molecular Mechanisms and Their Application on Oncolytic Newcastle Disease Virus in Cancer Therapy.

Cancer is caused by the destruction or mutation of cellular genetic materials induced by environmental or genetic factors. It is defined by uncontrolled cell proliferation and abnormality of the apoptotic pathways. The majority of human malignancies are characterized by distant metastasis and dissemination. Currently, the most common means of cancer treatment include surgery, radiotherapy, and chemotherapy, which usually damage healthy cells and cause toxicity in patients. Targeted therapy is an effective tumor treatment method with few side effects. At present, some targeted therapeutic drugs have achieved encouraging results in clinical studies, but finding an effective solution to improve the targeting and delivery efficiency of these drugs remains a challenge. In recent years, oncolytic viruses (OVs) have been used to direct the tumor-targeted therapy or immunotherapy. Newcastle disease virus (NDV) is a solid oncolytic agent capable of directly killing tumor cells and increasing tumor antigen exposure. Simultaneously, NDV can trigger the proliferation of tumor-specific immune cells and thus improve the therapeutic efficacy of NDV in cancer. Based on NDV's inherent oncolytic activity and the stimulation of antitumor immune responses, the combination of NDV and other tumor therapy approaches can improve the antitumor efficacy while reducing drug toxicity, indicating a broad application potential. We discussed the biological properties of NDV, the antitumor molecular mechanisms of oncolytic NDV, and its application in the field of tumor therapy in this review. Furthermore, we presented new insights into the challenges that NDV will confront and suggestions for increasing NDV's therapeutic efficacy in cancer.

Mesonephric-Like Adenocarcinoma of Uterine Corpus: A Clinicopathological and Targeted Genomic Profiling Study in a Single Institution.

Background: Mesonephric-like adenocarcinoma (MLA) is a recently characterized, rare, and aggressive neoplasm that mostly arises in the uterine corpus and ovary. MLA shows characteristic pathological features similar to mesonephric adenocarcinoma of the cervix. The origin of MLA is still controversial and recognition of it remains challenging for pathologists. The aim of this study was to enrich the clinicopathological features of MLA in the uterine corpus and explore its molecular alterations by targeted next-generation sequencing (NGS). Methods: Four cases of MLA were identified among a total of 398 endometrial carcinomas diagnosed in our institution between January 2014 and December 2021. Immunohistochemistry and targeted NGS spanning 437 cancer-relevant genes were performed. Results: The most common symptom was abnormal vaginal bleeding, and the average age was 68 years. Histologically, the tumors showed a mixture of varied growth patterns including papillary, glandular, tubular, cribriform, solid, and slit-like architectures, which were lined by columnar to cuboidal cells with overlapping vesicular nuclei and sometimes nuclear grooves. Intraluminal eosinophilic colloid-like secretions were focally evident in three of the four cases. Immunohistochemically, the MLAs were positive for GATA3 (4/4), TTF-1 (3/3), luminal CD10 (3/3), calretinin (2/3), and patchy P16 (3/3) and were negative for ER (0/4) and PR (0/4). The expression of P53 was "wild type" (4/4). By targeted NGS, 3/4 (75%), 2/4 (50%), and 1/4 (25%) cases harbored PIK3CA, KRAS, and PTEN mutations, respectively. None of the tumors had mutations in DNA mismatch repair genes, ARID1A/B, POLE, CTNNB1, SMARCA4, or TP53. At the time of diagnosis, three were presented with FIGO IB stage and one with IIIC stage. Two patients received postoperative chemotherapy and radiotherapy and they were alive without evidence of disease at 8 and 56 months follow-up, respectively. One patient developed pulmonary metastasis 13 months after surgery and chemotherapy, and one was dead of the disease 24 months after the operation without adjuvant therapy. Conclusions: MLA is a rare and aggressive malignancy, representing approximately 1% of all endometrial carcinomas. It exhibits mixed architectures associated with distinctive immunophenotype and recurrent KRAS and PIK3CA mutations, supporting classified as of Müllerian origin with mesonephric differentiation.

Angiofibroma of Soft Tissue: A Clinicopathological Study of Eight Cases With Emphasis on the Diagnostic Utility of Fluorescence In Situ Hybridization Detection for NCOA2 Rearrangement.

Background: Angiofibroma of soft tissue (AFST) is a rare mesenchymal neoplasm of fibroblastic differentiation. Due to its diverse morphology and the lack of specific immunohistochemistry (IHC) markers, AFST could elicit a broad range of differential diagnosis. Several studies have disclosed in AFST recurrent gene fusions involving NCOA2, mainly AHRR-NCOA2 fusion, providing a useful approach to diagnosing this lesion. We report eight additional cases of this rare entity with emphasis on the diagnostic utility of fluorescence in situ hybridization (FISH) detection for NCOA2 rearrangement. Methods: Clinicopathological data for eight AFSTs were retrieved. IHC was performed, and FISH was used to detect rearrangements involving NCOA2, DDIT3, and FUS loci. Results: There were five female and three male patients, ranging in age from 29 to 69 years (median: 55 years). The patients presented mostly with a slow-growing mass in the extremities, with or without intermittent pain. All tumors were located in the lower extremities with three (27.5%) involving or adjacent to the knee joints. Tumor size ranged from 1.5 to 3.8 cm (median: 3.0 cm). Morphologically, the tumors consisted of a proliferation of uniform, bland spindle cells set in alternating myxoid and collagenous stroma with a prominent vascular network composed of countless small, branching, thin-walled blood vessels. Foci of "chicken wire"-like capillaries and medium- to large-sized blood vessels with prominent staghorn morphology were evident in two and four cases, respectively. In addition, sheets of small round cells and foci of cystic changes were observed in one each case. Degenerative nuclear atypia was identified in three cases, while mitosis and tumor necrosis were absent. By IHC, the stromal cells were variably positive for epithelial membrane antigen, desmin, and CD68. By FISH analysis, seven out of eight cases (87.5%) showed NCOA2 rearrangement, and the remaining one had increased gene copy numbers of intact NCOA2; rearrangements involving FUS (0/4) and DDIT3 (0/3) were not identified in the cases analyzed. All tumors were surgically removed, and none had recurrence at follow-up from 5 to 73 months. Conclusions: FISH analysis for NCOA2 rearrangement represents a practical method for confirming the diagnosis of AFST on the basis of appropriate histomorphological backgrounds.

KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling.

Smad nuclear-interacting protein 1 (SNIP1) is a transcription repressor related to the TGF-ß signaling pathway and associates with c-MYC, a key regulator of cell proliferation and tumor development. Currently, the mechanism by which SNIP1 regulates tumorigenesis and cancer metastasis is unknown. Here, we identify that SNIP1 is a non-histone substrate of lysine methyltransferase KMT5A, which undergoes KMT5A-mediated mono-methylation to promote breast cancer cell growth, invasion and lung metastasis. Mechanistically, we show KMT5A-mediated K301 methylation of SNIP1 represents a sensing signal to release histone acetyltransferase KAT2A and promotes the interaction of c-MYC and KAT2A, and the recruitment of c-MYC/KAT2A complex to promoter of c-MYC targets. This event ultimately inhibits the Hippo kinase cascade to enhance triple-negative breast cancer (TNBC) metastasis by transcriptionally activating MARK4. Co-inhibition of KMT5A catalytic activity and YAP in TNBC xenograft-bearing animals attenuates breast cancer metastasis and increases survival. Collectively, this study presents an KMT5A methylation-dependent regulatory mechanism governing oncogenic function of SNIP1.

ARID1A deficient undifferentiated spindle cell and rhabdoid sarcoma of the prostate: report of a unique case with emphasis on diagnostic implications.

BACKGROUND: SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex functions collectively as a tumor suppressor and the inactivation of any of its constituent components is frequently associated with tumor initiation and/or progression. Most SWI/SNF deficient tumors share common rhabdoid morphology. ARID1A is the most frequently dysregulated SWI/SNF subunit in human cancer and inactivation of ARID1A is frequent across carcinomatous types while very rarely drives the tumorigenesis of sarcomas. Herein, we report a rare case of primary prostatic undifferentiated spindle cell sarcoma with focal rhabdoid morphology, harboring biallelic inactivation of ARID1A detected by next-generation sequencing with complete loss of ARID1A expression by immunohistochemistry. CASE PRESENTATION: The patient is a 58-year-old man who presented with dysuria and obstructive voiding symptoms for 3 month and was found to have a large, ill-defined, prostatic mass lesion with circumferential extension into the rectal wall on imaging studies. A needle biopsy showed a spindle cell undifferentiated sarcoma of the prostate and the patient was treated by chemotherapy of combined etoposide and cisplatin for 2 months. A subsequent imaging study showed that the tumor was significantly enlarged, and the patient underwent laparoscopically radical prostatectomy. Gross examination showed a disrupted, 10 × 7 × 5 cm, solid and cystic mass involving almost the entire prostate and sparing the seminal vesicle glands. Histologic examination showed that tumor was composed mainly of mildly atypical, oval to spindle-shaped cells, arranged in sheets and fascicles or herringbone-like patterns within a small amount of edematous to myxoid, vascularized stroma. Notably, groups of discohesive rhabdoid tumor cells with eccentric nuclei, prominent nucleoli, and abundant globular cytoplasm were observed. There were prominent mitotic figures, multifocal geographic necroses, and foci of lymphovascular invasion. Immunohistochemistry showed that the tumor cells were diffusely positive for TLE-1 and vimentin and focally positive for epithelial membrane antigen, AE1/3, Cam5.2, SATB2, and CD34 (all in less than 10% tumor cells). Next-generation sequencing showed biallelic inactivation mutation of ARID1A; the predicted inactivating effect of ARID1A deletion was confirmed by immunohistochemical staining. After the surgery, the patient received an alternative combined chemotherapy of doxorubicin and ifosfamide for 5 months. The patient died 9 months after initial presentation due to extensive abdominal metastases. CONCLUSIONS: We report an ARID1A deficient undifferentiated spindle cell and rhabdoid sarcoma of the prostate, adding to the growing spectrum of SWI/SNF driven undifferentiated sarcoma. Rhabdoid cells can be a helpful morphological clue for promoting molecular and immunohistochemical analyses for deficiency of SWI/SNF subunits, in the diagnostic workup of undifferentiated neoplasms featuring epithelioid or rhabdoid morphology.

Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy.

BACKGROUND: Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells. KEY SCIENTIFIC CONCEPTS OF REVIEW: Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems. AIM OF REVIEW: This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects.

TRIM32 promotes radioresistance by disrupting TC45-STAT3 interaction in triple-negative breast cancer.

Radioresistance is common in the treatment of triple-negative breast cancer (TNBC), but the molecular mechanisms involved remain unclear. Herein, we reveal that tripartite motif-containing protein 32 (TRIM32) is upregulated in TNBC and is negatively associated with survival of TNBC patients. Radiotherapy resulted in enhanced expression of TRIM32, whereas TRIM32 depletion reduced TNBC radioresistance in vitro and in vivo. Mechanistically, radiotherapy promoted the association between TRIM32 and nuclear STAT3, which suppressed TC45-induced dephosphorylation of STAT3, resulting in increased STAT3 transcriptional activation and TNBC radioresistance. Finally, we demonstrated that TRIM32 and STAT3 phosphorylation are co-expressed in TNBC tissues. Moreover, high expression of TRIM32 and STAT3 phosphorylation is positively linked to poor prognosis of TNBC patients. Our study demonstrates that TRIM32 is a novel target for predicting radioresistance in TNBC patients.