Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.

The role of insulinoma-associated protein 1 in predicting the progression and prognosis of human olfactory neuroblastoma in China.

OBJECTIVE: Recent studies have suggested that insulinoma-associated protein 1 (INSM1) is a useful marker for pathological diagnosis of neuroendocrine tumors. In the present study, we investigated the association between INSM1 expression and prognosis in patients with olfactory neuroblastoma (ONB) and assessed the usefulness of INSM1 as a prognostic biomarker in these patients. METHOD: Immunohistochemistry was performed on 109 ONB patients who underwent endoscopic surgery at Beijing Tong Ren Hospital (Beijing, China) between June 2006 and November 2021 Patient age at the time of surgery ranged from 10 months to 72 years (mean age, 43.55 ± 13.47 years). In total, 63 (57.8%) and 46 (42.2%) tumors occurred in male and female patients, respectively. The percentages of grade I-IV cases were 13.8% (15/109), 36.7% (40/109), 29.4% (32/109) and 20.2% (22/109), respectively. RESULTS: The expression rate (moderately/strongly positive) of INSM1 was significantly higher in high-grade (Ⅲ/Ⅳ; 83%; 45/54) than low-grade (Ⅰ/Ⅱ; 27%; 15/55) ONB cases. High expression levels of INSM1 were significantly positively associated with high pathological stage (p < 0.001), local recurrence, and death. Kaplan­Meier analysis revealed that patients with high INSM1 expression had significantly shorter disease­free survival (DFS) and mean survival (75.01 ± 10.71 vs. 158.56 ± 10.32) times, and shorter overall survival (OS). Multivariate Cox regression analysis revealed that INSM1 was an independent prognostic factor for DFS (HR: 4.963, 95%CI [2.11-10.84] p < 0.001) and OS (HR: 4.791, 95%CI [2.117-10.485], p < 0.001) after adjusting for sex, age, and tumor grade. In addition, INSM1 was an independent prognostic factor for DFS in patients treated with surgery (HR: 3.714, 95%CI [1.267-10.889], p = 0.017) and chemotherapy (HR: 5.574, 95%CI [1.584-19.612], p = 0.007). CONCLUSION: INSM1 expression had a positive association with the prognosis of patients with ONB and could serve as a prognostic biomarker in these patients.

Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall.

OBJECTIVE: To generalise the features of PANP in case of potential clinical and pathological pitfall of diagnosis. METHODS: Thirteen patients diagnosed as PANP were retrospectively analyzed in the Pathology Department of Capital Medical University from August 2014 to December 2019. Immunohistochemical staining with CD34, CK, Vim, Calponin, Ki67, Bcl-2, and STAT-6 was performed with envision-two steps method. RESULTS: PANP is a benign tumor presenting with gross variegated tan to gray soft fleshy tissue with foci of obvious hemorrhage and necrosis. The imaging shows internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. Vimentin (Vim) stain was consistently positive, while negative for CD34, STAT-6 and Bcl-2 (focal positive in two cases). Calponin and CK stain was positive in nine cases, respectively. CONCLUSION: PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment. LEVEL OF EVIDENCE: This work was Level 2 of evidence according to the Guide for Authors.

Machine learning method for the cellular phenotyping of nasal polyps from multicentre tissue scans.

BACKGROUND: This study aimed to establish a convenient and accurate chronic rhinosinusitis evaluation platform CRSAI 1.0 according to four phenotypes of nasal polyps. RESEARCH DESIGN AND METHODS: Tissue sections of a training (n = 54) and test cohort (n = 13) were sourced from the Tongren Hospital, and those for a validation cohort (n = 55) from external hospitals. Redundant tissues were automatically removed by the semantic segmentation algorithm of Unet++ with Efficientnet-B4 as backbone. After independent analysis by two pathologists, four types of inflammatory cells were detected and used to train the CRSAI 1.0. Dataset from Tongren Hospital were used for training and testing, and validation tests used the multicentre dataset. RESULTS: The mean average precision (mAP) in the training and test cohorts for tissue eosinophil%, neutrophil%, lymphocyte%, and plasma cell% was 0.924, 0.743, 0.854, 0.911 and 0.94, 0.74, 0.839, and 0.881, respectively. The mAP in the validation dataset was consistent with that of the test cohort. The four phenotypes of nasal polyps varied significantly according to the occurrence of asthma or recurrence. CONCLUSIONS: CRSAI 1.0 can accurately identify various types of inflammatory cells in CRSwNP from multicentre data, which could enable rapid diagnosis and personalized treatment.

Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall

Abstract Objective To generalise the features of PANP in case of potential clinical and pathological pitfall of diagnosis. Methods Thirteen patients diagnosed as PANP were retrospectively analyzed in the Pathology Department of Capital Medical University from August 2014 to December 2019. Immunohistochemical staining with CD34, CK, Vim, Calponin, Ki67, Bcl-2, and STAT-6 was performed with envision-two steps method. Results PANP is a benign tumor presenting with gross variegated tan to gray soft fleshy tissue with foci of obvious hemorrhage and necrosis. The imaging shows internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. Vimentin (Vim) stain was consistently positive, while negative for CD34, STAT-6 and Bcl-2 (focal positive in two cases). Calponin and CK stain was positive in nine cases, respectively. Conclusion PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment. Level of evidence: This work was Level 2 of evidence according to the Guide for Authors.

Secretory carcinoma of the sinonasal cavity and pharynx: A retrospective analysis of four cases and literature review.

Secretory carcinoma (SC) is a recently recognized type of salivary gland tumor characterized by t(12;15) (p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. Most SCs are located in a main salivary gland, and primary sinonasal secretary carcinoma is rare. We describe three cases of primary SC in the sinonasal cavity with high-grade transformation (HGT) in one case, and the first case in the pharynx. All tumors comprised slightly atypical cells with solid, tubular, microcystic growth patterns. The case with HGT included two components with distinct sharp boundaries and comedo necrosis, high mitotic figures and obvious cellular atypia. Tumor cells were positive for vimentin, S100, and Gata-3 and negative for p63 and DOG-1. Three cases showed nuclear staining of pan-TRK and one showed cytoplasmic staining. All cases harbored ETV6 gene rearrangement, and ETV6-NTRK3 gene fusion was detected in three cases. Most patients were treated with radical resection and adjuvant therapy. After excision, all remained tumor-free for 65-164 months (medium 98.5 months). SC in the sinonasal cavity and pharynx is a low-grade malignant tumor with histologic features overlapping those of other salivary gland tumors. Immunohistochemical analysis and fluorescence in situ hybridization are useful techniques for its differential diagnosis.

The role of α-smooth muscle actin in confirming the microinvasion of laryngeal squamous cell carcinoma.

BACKGROUND: The diagnosis of microinvasive laryngeal squamous cell carcinoma (LSCC) is not always straightforward and sometimes can be very challenge in daily clinical practice. The focus lies in the confirmation of microinvasion. Cancer-associated fibroblasts (CAFs), as the major element of reactive tumor stroma, are believed to participate actively in the growth and invasion of tumor cells. OBJECTIVES: To evaluate the diagnostic role of α-smooth muscle actin (α-SMA) labelling CAFs in microinvasive LSCC. METHODS: A total of 81 laryngeal biopsy specimens were retrieved, including 41 cases of microinvasive LSCC with depth of invasion no more than 3 mm, 20 laryngeal squamous intraepithelial lesion (SIL), and 20 benign pseudoepitheliomatous hyperplasia (PEH). All cases were stained for immunohistochemistry, using antibody against the α-SMA antigen. The correlation between the presence of CAFs in microinvasive LSCC and tumor histological characteristics was investigated. RESULTS: Immunoreactivity of α-SMA was detected in twenty-nine microinvasive LSCC (29/41, 71%), while no reactivity was observed in laryngeal SIL (0/20, 0%), and rarely in PEH (2/20, 10%). The α-SMA expression pattern in stroma of microinvasive LSCC was significantly different from that of SIL (χ2 = 26.966, p = 0.000) and PEH (χ2 = 19.838, p = 0.000). In addition, there seemed to be a certain correlation between the histological characteristics of microinvasive LSCC and the presence of interstitial CAFs. CONCLUSIONS: This study highlights the practical role of utilizing α-SMA in the pathological diagnosis of microinvasive LSCC, with emphasis on variable histomorphologic features of microinvasive LSCC.

Sinonasal low-grade non-intestinal-type adenocarcinoma: A retrospective analysis and literature review.

Sinonasal low-grade non-intestinal-type adenocarcinomas (LG non-ITACs) are uncommon tumors with unclear histogenesis, although they are presumed to arise from seromucous glands or respiratory epithelium. We investigated the clinicopathological and immunohistochemical features of the tumors, with particular attention to the transition area from the normal epithelium to neoplastic cells and concurrent lesions; these features were compared with those of 10 patients with chronic sinusitis, who served as a control group. Seventeen patients with LG non-ITACs (17 tumors) were enrolled in this retrospective study (9 male patients and 8 female patients; mean age, 48 years [range, 16-74 years]). Tumor cells continuous with respiratory epithelium were detected in 10 tumors composed of a single layer of cells with papillary, tubular, or cystic growth pattern. The tumor cells were uniformly cuboidal to columnar and polar. In seven tumors without transition areas discerned, three tumors consisted of polygonal and flat cells with a solid, acinar, micropapillary and cribriform pattern. The others had the same morphology as those with transition areas. The tumor cells were positive for SOX10 (15/17), S100 protein (8/17), and CK7 (17/17). The normal epithelium connected to the respiratory epithelium was the terminal duct in the control group. Except for the lack of p63-positive cells, the immunophenotype and histomorphology of transition areas with LG non-ITACs were similar to those of the continuous areas between the terminal duct and the respiratory epithelium in the control group. LG non-ITACs are seromucinous tumors, some of which may originate from the terminal ducts of seromucinous glands.

DOK7 Inhibits Cell Proliferation, Migration, and Invasion of Breast Cancer via the PI3K/PTEN/AKT Pathway.

Recently, increasing attention has been paid to the correlation between the expression of downstream of kinase 7 (DOK7) and the occurrence and development of various tumors. In this study, we clarified the effects of DOK7 in breast cancer. First, we showed that DOK7 expression was obviously reduced in the breast cancer tissues and lower levels of DOK7 linked to more aggressive behaviors and worse prognosis of patients. Furthermore, DOK7 expression of various breast cancer cell lines was lower than that of human noncancerous MCF-10A cells. Overexpression of DOK7 inhibited proliferation, migration, and invasion, while silencing DOK7 expression promoted the malignancy of breast cancer. In addition, overexpression of DOK7 suppressed tumor proliferation and lung metastasis in animal models. Finally, to investigate the possible signaling mechanism, we first found that the level of p-AKT protein was extremely downregulated and the level of PTEN protein was remarkably upregulated after overexpressing DOK7 in breast cancer cells. Repression of PTEN expression using PTEN siRNA or SF1670 (PTEN inhibitor) rescued the tumor-inhibiting effect induced by DOK7 overexpression, suggesting that DOK7 inhibits proliferation, migration, and invasion of breast cancer cells though the PI3K/PTEN/AKT pathway. These results suggest that the downregulation of DOK7 may become a novel breast cancer therapeutic target.

Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD-L1.

Mounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule-associated protein G3BP2 is involved in the regulation of tumor-initiating (stem) cells. In this study, we show that this protein also upregulates the immune checkpoint molecule PD-L1 under conditions of stress in breast and glioblastoma cancer cells, revealing a previously unknown connection between stemness programs, stress responses, and immune checkpoint control. We also identified a significant correlation between G3BP2 and PD-L1 co-expression in tumor tissues from cancer patients. To assess the targetability of G3BP2, we employed a small molecule (C108) that binds G3BP2 and interferes with the stress response. Tumors treated with C108 had increased CD8 T-cell proliferation and infiltration. Moreover, treatment of breast tumor-bearing mice with C108 resulted in a significant survival benefit and long-term cures. Cancer cells treated with C108 or cancer cells with genetically repressed G3BP2 had decreased PD-L1 expression due to enhanced mRNA degradation. Our study provides a compelling mechanism linking stress granule formation and immune checkpoint program of cancer, suggesting this link may provide new opportunities for improving anticancer immunotherapy.

A deep convolutional neural network-based method for laryngeal squamous cell carcinoma diagnosis.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is one of the most common tumors of the respiratory tract. Currently, the diagnosis of LSCC is mainly based on a laryngoscopy analysis and pathological findings. Deep-learning algorithms have been shown to provide accurate clinical diagnoses. METHODS: We developed a deep convolutional neural network (CNN) model, and evaluated its application to narrow-band imaging (NBI) endoscopy and pathological diagnoses of LSCC at several hospitals. A total of 4,591 patients' laryngeal NBI scans (1,927 benign and 2,664 LSCC) were used to test and validate the model. Additionally, 3,458 pathological images (752 benign and 2,706 LSCC) of 1,228 patients' hematoxylin and eosin staining slides (318 benign and 910 LSCC) were used for the pathological diagnosis training and validation. The images were randomly divided into training, validation and testing images at the ratio of 70:15:15. An independent test cohort of LSCC NBI scans and pathological images from other institutions were also used. RESULTS: In the NBI group, the areas under the curve of the validation, test, and independent test data sets were 0.966, 0.964, and 0.873, respectively, and those of the pathology group were 0.994, 0.981, and 0.982, respectively. Our method was highly accurate at diagnosing LSCC. CONCLUSIONS: In this study, the CNN model performed well in the NBI and pathological diagnosis of LSCC. More accurate and faster diagnoses could be achieved with the assistance of this algorithm.

Study of the Ultrasound Appearance of the Normal Parathyroid Using an Intraoperative Procedure.

OBJECTIVES: This study was designed to confirm the echogenicity of normal parathyroid glands using intraoperative ultrasound (US). METHODS: Between October 2015 and January 2016, normal parathyroid glands were examined with an intraoperative US transducer during thyroidectomy procedures in 13 patients with thyroid disease. According to the findings from intraoperative US, routine percutaneous US of normal parathyroid glands was performed in a group of adults. On the basis of previous information on normal parathyroid echogenicity, a series of parathyroid diseases that were proved by surgery and histopathologic analyses were retrospectively reviewed. The presence of residual normal parathyroid in the lesion on US imaging, which was defined as the residual parathyroid sign in this study, was reviewed and correlated with histopathologic results. RESULTS: In the intraoperative US group, 23 parathyroid glands were scanned intraoperatively, and 21 (91.3%) were hyperechoic, homogeneous in texture, and oval. In the routine percutaneous US group, 106 parathyroid glands were found in total, and 96 (90.5%) of the glands had hyperechoic and homogeneous echogenicity, with 75 (70.8%) being oval. In the review of parathyroid diseases, 33 parathyroid glands in 30 cases were reviewed, with a positive residual parathyroid sign in 7 (21.2%) parathyroid glands, presenting with a hyperechoic rim in the margin, and 4 of them (12.1%) were confirmed by histopathologic results. CONCLUSIONS: The normal parathyroid had hyperechoic echogenicity on both intraoperative and percutaneous US imaging. Residual tissue of parathyroid glands can also be observed in some parathyroid abnormalities with an echogenic appearance on US imaging and confirmed by histopathologic results.

Transcobalamin I: a novel prognostic biomarker of neoadjuvant chemotherapy in locally advanced hypopharyngeal squamous cell cancers.

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HPSCC) is an aggressive head and neck squamous cell carcinoma with poor prognosis. Neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiotherapy could provide better efficacy in HPSCC treatment. Identification of predictive biomarkers is critically needed to improve selection of patients who derive the most benefit from NACT. The aim of this study was to investigate whether transcobalamin I (TCN1) could be a novel predictive biomarker for NACT in HPSCC. METHODS: We collected biopsy specimens from 102 patients with primary locally advanced HPSCC. Messenger RNA (mRNA) and protein expression levels of TCN1 were analyzed using quantitative polymerase chain reaction and immunohistochemistry, respectively. The relationship between TCN1 expression, chemotherapy sensitivity, and clinical outcome was assessed using univariate Kaplan-Meier survival analyses and multivariate analysis with covariate adjustments. Furthermore, we knocked down TCN1 by small interfering RNA (siRNA) in HPSCC cell FaDu, tested the effects of TCN1 knockdown on cisplatin toxicity by MTT assay, and detected cisplatin-induced apoptosis by Western blotting. RESULTS: TCN1 expression was significantly lower in NACT-sensitive patients than nonsensitive patients at protein level (p=0.013) and mRNA level (p<0.001), indicating that low TCN1 expression predicts better NACT treatment response. Furthermore, TCN1 was an independent prognostic biomarker for both overall survival (p=0.047) and disease-free survival (p=0.05) in advanced HPSCC patients. In addition, in vitro experiments showed that genetic silencing of TCN1 using siRNA sensitized FaDu cells to cisplatin treatment with increased cell apoptosis. CONCLUSION: Low expression of TCN1 might be a novel prognostic biomarker for predicting NACT sensitivity and clinical outcome in local advanced HPSCC patients.

Immunoglobulin G4-related chronic rhinosinusitis: a pitfall in the differential diagnosis of granulomatosis with polyangiitis, Rosai-Dorfman disease, and fungal rhinosinusitis.

Immunoglobulin G4 (IgG4)-related chronic rhinosinusitis (CRS) has recently been proposed to be a new clinical entity of nasal disease, with no consensually agreed criteria for diagnosis. Moreover, the pathological features of IgG4-related CRS often overlap with other sinonasal inflammatory and autoimmune diseases such as granulomatosis with polyangiitis (GPA), Rosai-Dorfman disease (RDD) and fungal rhinosinusitis (FRS). We aimed to explore the specific similarities and differences in clinicopathologic features between IgG4-related CRS, and GPA, RDD and FRS, in order that these conditions can be diagnosed more accurately. Biopsy specimens collected from nasal mucosa of 20 IgG4-related CRS, 10 GPA, 10 RDD and 10 FRS patients were assessed by hematoxylin and eosin staining and immunohistochemical techniques for specific histochemical differences. The number of IgG4-positive plasma cells /high-power fields (HPF) in biopsies from IgG4-related CRS patients (mean=79.6±51.59; range=15/HPF to 230/HPF) was significantly higher than in biopsies from GPA (mean=13±9.428; P<.0001) and RDD (mean=12.5± 8.267; P<.0001) patients, but not from FRS (mean=47.4±26.48; P>.05) patients. Similarly, the ratio of IgG4/IgG-positive plasmacytes was >40% in 90% (18/20) of IgG4-related CRS patients, compared to >40% in 10% (1/10) of GPA patients, 20% (2/10) of RDD patients and 20% (2/10) of FRS patients. The sinonasal diseases GPA, RDD and FRS might present with similar histopathologic features such as the increased numbers of plasma cells and fibrosis, which are characteristic of IgG4-related CRS. A comprehensive consideration combining the clinical signs and symptoms with a histopathological assessment of IgG4-positive plasma cells may provide accurate diagnoses of these conditions.

Sonography used in the infantile desmoid fibromatosis of postcricoid area: A case report.

RATIONALE: Infantile desmoid fibromatosis of the postcricoid area is a rare disease and is characterized by a proliferation of fibrous tissue with non-metastasis, local infiltration, and a high rate of recurrence after surgical resection. Currently, ultrasound is scarcely used in the hypopharynx and larynx area. PATIENT CONCERNS: A 4-year-old boy presented with hoarseness, deep voice and snoring for 2∼4 years without any surgical history. On sonography, the lesion was found in the postcricoid area, and the left larynx showed impaired mobility in real time observation. Complete excision with a negative margin in this pivotal anatomic area is impossible, and necessitates a long-time surveillance. DIAGNOSES: Infantile desmoid fibromatosis of the postcricoid area was diagnosed according to surgery and histopathology. INTERVENTIONS: Local excision was carried out to relieve the upper airway narrowing. OUTCOMES: Relieved hoarseness and snoring were reported on the latest follow-up. A residual lesion was seen in the surgical bed and maintained a stable extent on ultrasound and MR imaging after a year. LESSONS: Considering the non-radiation merit and diagnostic ability, ultrasonography is advocated as a valuable supplementary imaging method to CT, MR and laryngoscopy in the juvenile larynx and hypopharynx.

SLC7A11, a component of cysteine/glutamate transporter, is a novel biomarker for the diagnosis and prognosis in laryngeal squamous cell carcinoma.

Solute carrier family 7, membrane 11 (SLC7A11) or (xCT) is a component of the cysteine-glutamate transporter, which plays a critical role in glutathione homeostasis which is important to protect cells from oxidative stress. SLC7A11 is distributed in various tissues and participates in the occurrence of a number of diseases, particularly in the pathogenesis of malignant tumors, but its role in laryngeal cancer development has not yet been clearly defined. The objective of the present study was to investigate the role of SLC7A11 in laryngeal squamous cell carcinoma (LSCC). We conducted immunohistochemistry and RT-PCR to evaluate the protein and mRNA levels of SLC7A11 in LSCC and in control tissues, respectively. The knockdown experiments were conducted with SLC7A11 short hairpin RNA (shRNA) lentivirus, and the protein and mRNA levels of SLC7A11 were assessed by RT-PCR and western blotting. The functional study of SLC7A11 in vitro was conducted by MTT assay, and the effects on the cell cycle were detected using flow cytometry. Immunohistochemical results revealed that the expression levels of SLC7A11, Ki-67 and p53 in LSCC tissues were higher than those in laryngeal dysplasia tissues. The Spearman rank correlation analysis revealed that the expression of SLC7A11 was positively correlated with the expression of p53 and Ki-67. Cox regression analysis and Kaplan-Meier plots confirmed that the expression levels of SLC7A11 were a prognostic factor for overall survival (OS) rates and postoperative recurrence of LSCC. Moreover, the functional study of SLC7A11 in vitro revealed that knockdown of SLC7A11 using shRNA inhibited cell proliferation by inducing cell cycle arrest at the G1 phase. Immunohistochemical and RT-PCR results and knockdown experiments of SLC7A11 revealed that SLC7A11 was involved in the progression of LSCC, and may provide clinical information for the evaluation of OS rates and postoperative recurrence of LSCC. Collectively, these observations suggest that SLC7A11 may be a vital biomarker for the diagnosis and prognosis in human LSCC, and targeting SLC7A11 appears to be a potentially significant method for LSCC treatment.

Class III ß-Tubulin in Colorectal Cancer: Tissue Distribution and Clinical Analysis of Chinese Patients.

BACKGROUND Class III ß-tubulin (ßIII-tubulin) has been reported to express at the invasive margin of colorectal cancer. The present study aimed to investigate the clinical implication of ßIII-tubulin expression at the invasive margin of colorectal cancer. MATERIAL AND METHODS We recruited 111 patients with surgically resected colorectal carcinoma for bIII-tubulin expression analysis. The cases with bIII-tubulin-positive tumor cells found only in the invasive front tumor area were assigned to the invasive front group, while the remaining cases were all assigned to the non-invasive front group. Clinical analysis of ßIII-tubulin and other clinical data was performed. RESULTS The positive staining rates and staining intensity of bIII-tubulin were significantly different between the invasive and non-invasive front groups (p=0.001 and p=0.006), and there was a significant difference in tumor differentiation between the 2 groups (p=0.032). In the non-invasive front group, staining intensity of bIII-tubulin was significantly associated with positive staining rates and lymphatic metastasis (p<0.001 and p=0.048). CONCLUSIONS Our data showed the tissue distribution of bIII-tubulin expression at invasive margin or diffuse distribution. Expression of bIII-tubulin was correlated with tumor differentiation and lymphatic metastasis, suggesting a potential role of bIII-tubulin in tumor differentiation and metastasis. This study may shed light on bIII-tubulin as a novel potential molecular target for a new anti-cancer drug.

Inhibition of choroidal neovascularization by lentivirus-mediated PEDF gene transfer in rats.

AIM: To evaluate the effects of lentivirus-mediated pigment epithelium-derived factor (PEDF) gene transfer performed in treatment of rats with established choroidal neovascularization (CNV), and investigates the mechanism by which PEDF inhibits CNV in rats. METHODS: Brown Norway (BN) rats (n=204) were induced by exposure to a laser, and then randomly assigned to 3 groups: no treatment; treatments with intravitreal injection of lentivirus-PEDF-green fluorescent protein (GFP) or lentivirus-control GFP (free fluorescent protein). Following induction and treatment, the CNV tissue was assessed for form, size and vessel leakage by fluorescein fundus angiography (FFA), optical coherence tomography (OCT), histopathology, and examination of choroidal flat mounts. VEGF, Flk-1, and PEDF expression were evaluated by real-time polymerase chain reaction (PCR) and Western blot. RESULTS: A stable laser-induced rat model of CNV was successfully established, and used to demonstrate lentivirus-mediated PEDG gene transfer by intravitreal injection. Expression of green fluorescence labelled PEDF was observed in the retina up to 28d after injection. An intravitreal injection of lentivirus-PEDF-GFP at 7d led to a significant reduction in the size, thickness and area of CNV showed by FFA, OCT and choroidal flat mounts. PEDF was up-regulated while VEGF and Flk-1 were down-regulated in the lentivirus-PEDF-GFP group. The differences in VEGF and Flk-1 expression in the control and lentivirus-PEDF groups at 7, 14, 21 and 28d after laser induction were all statistically significant. CONCLUSION: Lentivirus-mediated PEDF gene transfer is effective for use in treatment of laser-induced CNV, and PEDF exerts its therapeutic effects by inhibiting expression of VEGF and Flk-1.

[IgG4-related sialodacryoadenitis and chronic rhinosinusitis: a clinicopathologic analysis of 13 cases].

OBJECTIVE: To study the clinicopathologic characteristics of IgG4-related sialodacryoadenitis and chronic rhinosinusitis (CRS). METHODS: A total of 13 patients (patient group) were evaluated clinically and biopsy specimens from the lacrimal/salivary glands (n=12) and nasal mucosa (n=8) were reviewed and immunohistochemistry was performed to assess IgG-and IgG4-positive cells. Similarly, nine patients with IgG4-related sialodacryoadenitis without CRS and 10 patients with common CRS were included as controls. RESULTS: There were 8 male patients and 5 female patients. The age of patients ranged from 32 to 71 years (mean 50.2 years). The patient group had higher serum IgG4 concentration than that of the control group (P<0.05). Lymphoplasmacytic infiltration, lymphoid follicle formation and sclerosis were prominent in lacrimal/salivary glands in both groups; however the magnitude of IgG4-positive plasmacytic infiltration in the patient group was significantly higher than that of the control group (P<0.05). Similarly, evaluation of nasal mucosa revealed greater lymphocytic and plasmacytic infiltration, and lymphoid follicle formation, together with significantly higher amount of IgG4-positive plasma cell infiltration in the patient group compared to the common CRS group (P<0.05). CONCLUSIONS: IgG4-related disease (IgG4-RD) simultaneously involving lacrimal/salivary glands and nasal cavity/paranasal sinuses is rare and characterized by a combination of IgG4-positive plasma cell infiltration involving lacrimal/salivary glands and nasal mucosa along with an increased serum level of IgG4. As a systemic disease, early and accurate diagnosis is therefore of great importance, and unnecessary surgery should be avoided.

Concomitant occurrence of Mikulicz's disease and immunoglobulin G4-related chronic rhinosinusitis: a clinicopathological study of 12 cases.

AIMS: Concomitant occurrence of Mikulicz's disease (MD) and immunoglobulin (Ig)G4-related chronic rhinosinusitis (IgG4-related CRS) is extremely rare. We evaluated the clinicopathological features of MD patients with concomitant IgG4-related CRS (CRS-MD). METHODS AND RESULTS: Twelve CRS-MD patients were evaluated clinically and biopsy samples were taken from the lacrimal/salivary glands (n = 12) and nasal mucosa (n = 7) for assessment of IgG4-positive cells, using immunohistochemical techniques. Similarly, nine MD patients and 10 patients with common CRS were evaluated as controls. CRS-MD patients had higher serum IgG and IgG4 concentrations than MD patients (P < 0.05 for both). Lymphoplasmacytic infiltration, lymphoid follicle formation and sclerosis was prominent in the lacrimal/salivary glands in both groups; however, the magnitude of IgG4-positive plasma cells infiltration in the CRS-MD group was significantly higher compared to the MD group (P = 0.004). Similarly, evaluation of nasal mucosa revealed greater lymphocyte, plasma cell and eosinophil infiltration and lymphoid follicle formation, together with significantly higher IgG4-positive plasma cell infiltration in the CRS-MD group compared to the common CRS group (P = 0.004). CONCLUSIONS: Concomitant MD and IgG4-related CRS were characterized by a combination of IgG4-positive plasma cells infiltration in the lacrimal/salivary glands and the nasal mucosa and increased serum IgG4.