Clinicopathological characteristics of placental chorioangioma: A clinicopathological study of 30 cases.

OBJECTIVE: The objective is to explore clinicopathological characteristics, diagnosis, differential diagnoses, treatment, and prognoses of placental chorioangioma (PCA). MATERIALS AND METHODS: The pathological data of 30 cases of PCA were collected; the color Doppler ultrasound, Down's screening, fetal survival, and pathological characteristics were observed; and the literature was reviewed. RESULTS: Of the 30 patients, the ages ranged from 20 to 38 years, with an average of 29.6 years. Pregnancy comorbidity occurred in 14 patients; intrauterine fetal death occurred in 4; the gross appearance of the tumor: a reddish-brown nodule, slightly round, 0.5-8 cm in diameter, can be seen on the cut surface of the placenta Pregnancy comorbidity occurred in 14 patients and intrauterine fetal death in 4. On sectioning the placenta, tumors grossly appeared as reddish-brown nodules, slightly round and ranging in diameter from 0.5 to 8 cm. Microscopically, the tumor has small, densely packed capillaries with fibrous connective tissue in the stroma. There were 10 cases with high risk of Down's syndrome screening, and the immunophenotype CD34 (+) and Ki-67 proliferation index were less than 10%. CONCLUSIONS: PCA is rare and may be misdiagnosed as malignant tumor, which may be related to pregnancy comorbidity and high risk of Down's screening, so improving the understanding of PCA can provide the basis for clinical diagnosis and intervention. PCA is a rare tumor which may be misdiagnosed as a malignancy. It may be related to pregnancy comorbidity and high risk of Down's screening. Improving the understanding of PCA could provide the basis for clinical diagnosis and intervention.

Clearance phagocytosis by the retinal pigment epithelial during photoreceptor outer segment renewal: Molecular mechanisms and relation to retinal inflammation.

Mammalian photoreceptor outer segment renewal is a highly coordinated process that hinges on timed cell signaling between photoreceptor neurons and the adjacent retinal pigment epithelial (RPE). It is a strictly rhythmic, synchronized process that underlies in part circadian regulation. We highlight findings from recently developed methods that quantify distinct phases of outer segment renewal in retinal tissue. At light onset, outer segments expose the conserved "eat-me" signal phosphatidylserine exclusively at their distal, most aged tip. A coordinated two-receptor efferocytosis process follows, in which ligands bridge outer segment phosphatidylserine with the RPE receptors αvß5 integrin, inducing cytosolic signaling toward Rac1 and focal adhesion kinase/MERTK, and with MERTK directly, additionally inhibiting RhoA/ROCK and thus enabling F-actin dynamics favoring outer segment fragment engulfment. Photoreceptors and RPE persist for life with each RPE cell in the eye servicing dozens of overlying photoreceptors. Thus, RPE cells phagocytose more often and process more material than any other cell type. Mutant mice with impaired outer segment renewal largely retain functional photoreceptors and retinal integrity. However, when anti-inflammatory signaling in the RPE via MERTK or the related TYRO3 is lacking, catastrophic inflammation leads to immune cell infiltration that swiftly destroys the retina causing blindness.

Placental mesenchymal dysplasia: A case report and review of literature.

ABSTRACT: Placental mesenchymal dysplasia is a rare disorder of the placenta with only a few reported cases. A case of interstitial dysplasia of the placenta was reported. The diagnosis and differential diagnosis were made by gross observation, microscopic findings, and immunohistochemistry.

Glomus tumor of the crissum: A case report and review of literature.

Glomus tumor is a rare mesenchymal neoplasm arising from the modified smooth muscle cells of the glomus body. Primary crissum glomus tumor is extremely rare without any published in the literature. In this article, we report the first case of primary crissum glomus tumor in an 80-year-old man with recurrent anal pain for 8 years, increased pain for 1 year. Rectal MRI for inflammatory lesions (sinus tract). Microscopic examination showed the tumor cells were arranged in sheets and nests, surrounding blood vessels and nerve bundles. At high magnification, the neoplastic cells show regular round shape with light eosinophilic and translucent cytoplasm. The cell boundary is clear, the nucleus is round and located in the center. The stroma of the tumor shows hyaline degeneration. Immunohistochemically, the tumor cells were positive for smooth muscle actin, h-caldesmon, Calponin, synaptophysin, Collagen IV and CD34, but completely negative for HMB45, S100, EMA, desmin, CgA and CD56. The histologic features and immunohistochemical profile supported a diagnosis of primary crissum glomus tumor. The patient was asymptomatic and disease free after the procedure.

Acute RhoA/Rho Kinase Inhibition Is Sufficient to Restore Phagocytic Capacity to Retinal Pigment Epithelium Lacking the Engulfment Receptor MerTK.

The diurnal phagocytosis of spent photoreceptor outer segment fragments (POS) by retinal pigment epithelial (RPE) cells is essential for visual function. POS internalization by RPE cells requires the assembly of F-actin phagocytic cups beneath surface-tethered POS and Mer tyrosine kinase (MerTK) signaling. The activation of the Rho family GTPase Rac1 is necessary for phagocytic cup formation, and Rac1 is activated normally in MerTK-deficient RPE. We show here that mutant RPE lacking MerTK and wild-type RPE deprived of MerTK ligand both fail to form phagocytic cups regardless of Rac1 activation. However, in wild-type RPE in vivo, a decrease in RhoA activity coincides with the daily phagocytosis burst, while RhoA activity in MerTK-deficient RPE is constant. Elevating RhoA activity blocks phagocytic cup formation and phagocytosis by wild-type RPE. Conversely, inhibiting RhoA effector Rho kinases (ROCKs) rescues both F-actin assembly and POS internalization of primary RPE if MerTK or its ligand are lacking. Most strikingly, acute ROCK inhibition is sufficient to induce the formation and acidification of endogenous POS phagosomes by MerTK-deficient RPE ex vivo. Altogether, RhoA pathway inactivation is a necessary and sufficient downstream effect of MerTK phagocytic signaling such that the acute manipulation of cytosolic ROCK activity suffices to restore phagocytic capacity to MerTK-deficient RPE.

Drug repurposing strategies in the development of potential antifungal agents.

The morbidity and mortality caused by invasive fungal infections are increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is a potential way of expanding the application of existing drugs. Recently, various existing drugs have been shown to be useful in the prevention and treatment of invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up-to-date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field. KEY POINTS: • Conventional antifungal agents have limitations due to the occurrence of drug-resistant strains. • Non-antifungal drugs act as antifungal agents in various ways toward different targets. • Non-antifungal drugs with antifungal activity are demonstrated as effective antifungal strategies.

Smooth muscle tumor of uncertain malignant potential (STUMP): a clinicopathologic analysis of 26 cases.

BACKGROUND: To investigate the clinicopathologic features, differential diagnosis, and factors associated with recurrence in patients with smooth muscle tumors of uncertain malignant potential (STUMP). METHODS: The clinical and pathologic data of STUMP patients diagnosed in Mindong Hospital of Ningde City from 2017 to 2018 were collected and slides reviewed, the high-frequency color Doppler ultrasound and pathological characteristics were observed, and the literature was reviewed. RESULTS: All the STUMP diagnoses were confirmed by slide review. The age of onset was 23-61 years (mean 42.96 years). The main clinical symptoms were leiomyoma of uterus, prolonged menstruation, and increased menstruation. Color Doppler ultrasonography showed hypoechoic uterine wall nodules. The mean follow-up time was 62.9 months (range: 13-96 months). CONCLUSIONS: Smooth muscle tumors of undetermined malignant potential (STUMP) in the uterus are one of the rare gynecologic neoplasms. Although not malignant, they should be considered as low malignant potential tumors because they occasionally recur. Six of 13 recurrent tumors recurred in the years following hysterectomy with preservation. These six recurrent tumors are the only ones that had a strong immune response to p16 and p53. In support of early observation, these markers may help predict STUMP behavior. Patients diagnosed with STUMP should be monitored over time.

[High expression of activated CD4+ memory T cells and CD8+ T cells and low expression of M0 macrophage are associated with better clinical prognosis in bladder cancer patients].

Objective To study the infiltration pattern of bladder cancer immune cells and explore the relationship between immune cells and tumor prognosis. Methods The bladder cancer transcript data and corresponding clinical data were downloaded from The Cancer Genome Atlas (TCGA). CIBERSORT software deconvolution method was used to calculate the proportions of 22 kinds of immune cells. R software was used to analyze the immune cell infiltration pattern in each clinical stage. The relationship between each immune cell and prognosis was analyzed by Kaplan-Meier survival. Results A total of 433 cases of gene transcript data were downloaded from the TCGA database, including 414 cases of bladder cancer tissues and 19 normal tissues. After the data were corrected, the proportions of immune cells were calculated using CIBERSORT software. Screening was performed, and 146 cases of bladder cancer tissue and 4 cases of normal bladder tissue were obtained. Activated CD4+ memory T cells and CD8+ T cells had the lowest expression and M0 macrophages had the highest expression in clinical stage IV of bladder cancer. The bladder cancer patients with high expression of activated CD4+ memory T cells, CD8+ T cells and low expression of M0 macrophages had beneficial prognosis. Conclusion The bladder cancer patients with high expression of activated CD4+ memory T cells, CD8+ T cells and low expression of M0 macrophages might have better clinical prognosis.

Etv transcription factors functionally diverge from their upstream FGF signaling in lens development.

The signal regulated transcription factors (SRTFs) control the ultimate transcriptional output of signaling pathways. Here, we examined a family of FGF-induced SRTFs - Etv1, Etv 4, and Etv 5 - in murine lens development. Contrary to FGF receptor mutants that displayed loss of ERK signaling and defective cell differentiation, Etv deficiency augmented ERK phosphorylation without disrupting the normal lens fiber gene expression. Instead, the transitional zone for lens differentiation was shifted anteriorly as a result of reduced Jag1-Notch signaling. We also showed that Etv proteins suppresses mTOR activity by promoting Tsc2 expression, which is necessary for the nuclei clearance in mature lens. These results revealed the functional divergence between Etv and FGF in lens development, demonstrating that these SRTFs can operate outside the confine of their upstream signaling.

Many cells contain proteins known as signal-induced transcription factors, which are poised to receive messages from the environment and then react by activating genes required for the cell to respond appropriately. It is commonly thought that these transcription factors faithfully follow the instructions they receive from the external signal: for instance, if the message was to encourage the cell to grow, the transcription factors would switch on growth-related genes. As the eyes of mice and other mammals develop, a signal known as FGF is required for certain cells to specialize into lens fiber cells: these long, thin, transparent cells form the bulk of the lens, the structure that allows focused vision. Previous studies suggest that FGF activates three transcription factors known as Etv1, Etv4 and Etv5, but their precise roles in the development of the lens has remained unclear. Here, Garg, Hannan, Wang et al. confirm that FGF signaling does indeed activate all three proteins. However, mutant mice that lacked Etv1, Etv4 and Etv5 still created lens fiber cells, suggesting that the transcription factors are largely unnecessary for lens fiber cells formation. Instead, the Etv proteins participated in a cascade of molecular events involving a protein called Notch; as a result, if the transcription factors were absent, the lens fiber cells formed prematurely. In addition, deactivating Etv1, Etv4 and Etv5 also promoted the activity of a protein which interfered with the removal of internal cell compartments, a process required for lens fiber cells to mature properly. These findings reveal that the roles of Etv1, Etv4 and Etv5 deviate from and even oppose FGF signaling in the lenses of mice. Transcription factors control the ultimate fate of a cell, and there is therefore increased interest in targeting them for therapy. The work by Garg, Hannan, Wang et al. reveals an unexpected complexity in how these proteins respond to upstream signals, highlighting the importance of further dissecting these relationships.

Lens differentiation is controlled by the balance between PDGF and FGF signaling.

How multiple receptor tyrosine kinases coordinate cell fate determination is yet to be elucidated. We show here that the receptor for platelet-derived growth factor (PDGF) signaling recruits the p85 subunit of Phosphoinositide 3-kinase (PI3K) to regulate mammalian lens development. Activation of PI3K signaling not only prevents B-cell lymphoma 2 (BCL2)-Associated X (Bax)- and BCL2 Antagonist/Killer (Bak)-mediated apoptosis but also promotes Notch signaling to prevent premature cell differentiation. Reducing PI3K activity destabilizes the Notch intracellular domain, while the constitutive activation of Notch reverses the PI3K deficiency phenotype. In contrast, fibroblast growth factor receptors (FGFRs) recruit Fibroblast Growth Factor Receptor Substrate 2 (Frs2) and Rous sarcoma oncogene (Src) Homology Phosphatase 2 (Shp2) to activate Mitogen-Activated Protein Kinase (MAPK) signaling, which induces the Notch ligand Jagged 1 (Jag1) and promotes cell differentiation. Inactivation of Shp2 restored the proper timing of differentiation in the p85 mutant lens, demonstrating the antagonistic interaction between FGF-induced MAPK and PDGF-induced PI3K signaling. By selective activation of PI3K and MAPK, PDGF and FGF cooperate with and oppose each other to balance progenitor cell maintenance and differentiation.

Crk proteins transduce FGF signaling to promote lens fiber cell elongation.

Specific cell shapes are fundamental to the organization and function of multicellular organisms. Fibroblast Growth Factor (FGF) signaling induces the elongation of lens fiber cells during vertebrate lens development. Nonetheless, exactly how this extracellular FGF signal is transmitted to the cytoskeletal network has previously not been determined. Here, we show that the Crk family of adaptor proteins, Crk and Crkl, are required for mouse lens morphogenesis but not differentiation. Genetic ablation and epistasis experiments demonstrated that Crk and Crkl play overlapping roles downstream of FGF signaling in order to regulate lens fiber cell elongation. Upon FGF stimulation, Crk proteins were found to interact with Frs2, Shp2 and Grb2. The loss of Crk proteins was partially compensated for by the activation of Ras and Rac signaling. These results reveal that Crk proteins are important partners of the Frs2/Shp2/Grb2 complex in mediating FGF signaling, specifically promoting cell shape changes.

Sclerosing rhabdomyosarcoma presenting on the knee-joint.

Sclerosing rhabdomyosarcoma is a rare pathological diagnosis that easily misdiagnosed. The majority of cases reported the tumor increased rapidly in size and the Ki-67 proliferation index ranged from 10% to 60%. Here, we report the first case of the tumor increased very slowly for 20 years and the Ki-67 proliferation index was lower than 2%, and discuss its histological features and immunohistochemical reactivity with Desmin and Ki-67 and so on.

Essential diurnal Rac1 activation during retinal phagocytosis requires αvß5 integrin but not tyrosine kinases focal adhesion kinase or Mer tyrosine kinase.

Diurnal phagocytosis of shed photoreceptor outer-segment particles by retinal pigment epithelial (RPE) cells belongs to a group of conserved clearance mechanisms employing αv integrins upstream of tyrosine kinases and Rho GTPases. In this study, we tested the interdependence of the tyrosine kinases focal adhesion kinase (FAK) and Mer tyrosine kinase (MerTK) and Rho GTPases during engulfment. RPE cells activated and redistributed Rac1, but not RhoA or Cdc42, during phagocytosis. Toxin B, overexpression of dominant-negative Rac1, or decreasing Rac1 expression prevented particle engulfment. Fluorescence microscopy showed that Rac1 inhibition had no obvious effect on F-actin arrangement in resting RPE but prevented recruitment of F-actin to surface-bound phagocytic particles. Quantification of active GTP-Rac1 in wild-type and mutant RPE in culture and in vivo revealed that Rac1 activation during phagocytosis requires αvß5 integrin and its ligand milk fat globule EGF factor-8 (MFG-E8) but not the receptor tyrosine kinase MerTK. Abolishing tyrosine kinase signaling downstream of αvß5 toward MerTK by inhibiting FAK specifically or tyrosine kinases generally neither prevented Rac1 activation nor F-actin recruitment during phagocytosis. Likewise, inhibiting Rac1 had no effect on FAK or MerTK activation. We conclude that MerTK activation via FAK and F-actin recruitment via Rac1 both require MFG-E8-ligated αvß5 integrin. Both pathways are independently activated and required for clearance phagocytosis.

[Evaluation of immunohistochemistry staining and cytologic diagnosis by using cell block sections prepared with effusion fluid cytology specimens].

OBJECTIVE: To study the values of immunohistochemistry staining and cytological diagnosis by using cell block sections prepared with the effusion fluid cytology specimens. METHODS: Ninety-nine effusion cytology specimens with the diagnoses of reactive mesothelial hyperplasia, atypical cells and metastatic carcinoma were enrolled into the study. The cytospin preparations/smears, cell block sections and immunohistochemical study were performed and correlated with the clinical findings and follow-up data. RESULTS: Amongst the 99 cases studied, the percentage with positive diagnosis using cytospin preparations/smears was 68.7% (68/99). The percentages with negative and equivocal diagnoses were 16.2% (16/99) and 15.1% (15/99), respectively. As for cell block sections, the percentages were 71.7% (71/99), 16.2% (16/99) and 12.1% (12/99), respectively. On the other hands, the percentages became 76.8% (76/99), 20.2% (20/99) and 3.0% (3/99), respectively, when coupled with immunohistochemical findings. The overall percentages of positive, negative and equivocal diagnoses were 77.8% (77/99), 17.2% (17/99) and 5.0% (5/99), respectively, upon clinicopathologic correlation. The difference between cytospin preparations/smears and cell block sections was not statistically significant (P > 0.05). When coupled with immunohistochemical findings or clinicopathologic correlation, the difference in rates of equivocal diagnosis however carried statistical significance (P < 0.05). The false-negative rate of immunohistochemical study applied on cell block sections was 1.0% (1/99). CONCLUSIONS: Immunohistochemistry, when applied on cell block sections, is useful in delineation of the primary origins of the tumor cells in effusion fluid cytology specimens. Combination of morphologic examination, immunohistochemical findings and clinicopathologic correlation can further improve the rate of positive diagnosis.