Pemigatinib, a selective FGFR inhibitor overcomes ABCB1-mediated multidrug resistance in cancer cells.

P: -glycoprotein (P-gp/ABCB1) overexpression is one of the primary causes of multidrug resistance (MDR). Therefore, it is crucial to discover effective pharmaceuticals to combat multidrug resistance mediated by ABCB1. Pemigatinib is a selective the fibroblast growth factor receptor (FGFR) inhibitor that is used to treat a variety of solid tumors, Clinical Trials for Urothelial Carcinoma (NCT02872714) completed its research on Pemigatinib. This study aimed to determine whether Pemigatinib can reverse ABCB1-mediated multidrug resistance, as well as its mechanism of action. Pemigatinib substantially reversed ABCB1-mediated multidrug resistance, as determined by a CCK8 assay, and immunofluorescence experiments revealed that Pemigatinib had no effect on the intracellular localization of ABCB1. Pemigatinib was discovered to increase intracellular drug accumulation, thereby reversing multidrug resistance. In addition, Docking analysis revealed that Pemigatinib and ABCB1 have a high affinity for one another. This study concludes that Pemigatinib is capable of reversing the multidrug resistance mediated by ABCB1, offering ideas and references for the clinical application of Pemigatinib.

Safety and Efficacy of Placenta-Derived Mesenchymal Stem Cell Treatment for Diabetic Patients with Critical Limb Ischemia: A Pilot Study.

AIM: Diabetic foot has become the main cause of non-traumatic amputation. Stem cell therapy, especially mesenchymal stem cells (MSCs), holds a great promise as a therapy for diabetic foot with ischemia limb arterial disease. The aim of this pilot study is to evaluate the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment for diabetic patients with critical limb ischemia (CLI). METHODS: Four eligible diabetic patients with CLI were consecutively enrolled in this pilot study. On the base of the standard-of-care treatment, these patients accepted P-MSCs treatment by intramuscular injection for successive 3 times at an interval of 4 weeks, and the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment were evaluated. RESULTS: There were no serious adverse events during the period of P-MSCs injection and the 24-weeks follow-up period. The clinical ischemic features of patients were improved 24 weeks after P-MSCs treatment. The scores of resting pain and limb coldness significantly decreased, and pain-free walking distance significantly increased from baseline to 24 weeks after P-MSCs therapy. The resting ankle brachial index increased, but no statistically significant difference was found. The findings of magnetic resonance angiography showed the increase of collateral vessel formation in one patient, but there were no significant changes observed in the other patients. CONCLUSIONS: The data in this pilot study indicated that multiple intramuscular P-MSCs injections may be a safe and effective alternative therapy for diabetic patients with CLI, and larger, placebo-controlled, perspective studies are needed to prove these results.

Metformin improves survival in lung cancer patients with type 2 diabetes mellitus: A meta-analysis.

BACKGROUND AND OBJECTIVE: In recent years, many studies have investigated metformin and its effects on lung cancer. However, since previous studies have shown that the relationship between metformin and lung cancer is complicated, we performed a meta-analysis to analyze this relationship. MATERIAL AND METHODS: An electronic database search was conducted using PubMed, Embase, and Cochrane library. Outcomes were quantified with hazard ratios and 95% confidence intervals to compare lung cancer survival in patients treated with or without metformin. RESULTS: Ten studies, involving 4397 participants, were included. In the pooled analysis, we found that metformin treatment significantly improved the survival of lung cancer patients (hazard ratio=0.75, 95% confidence interval: 0.70-0.80; P<0.001). Subgroup analysis showed that when stratified by geographic region, the hazard ratios for overall survival were 0.76 (95% confidence interval: 0.71-0.81, P<0.001) and 0.51 (95% confidence interval: 0.25-0.78, P<0.001) for Western and Asian countries, respectively. When stratified by lung cancer subtype, the hazard ratios for overall survival were 0.78 (95% confidence interval: 0.71-0.84, P<0.001), 0.73 (95% confidence interval: 0.66-0.81, P<0.001), and 0.51 (95% confidence interval: 0.25-0.78, P<0.001) for non-divided, non-small cell, and small-cell lung cancer subtypes, respectively. When stratified by study design, the hazard ratios for overall survival were 0.77 (95% confidence interval: 0.71-0.83, P<0.001) and 0.71 (95% confidence interval: 0.63-0.80, P<0.001) for cohort-based and case-controlled studies, respectively.

Metformin Use Is Associated with Reduced Incidence and Improved Survival of Endometrial Cancer: A Meta-Analysis.

Studies have suggested that metformin can potentially decrease the incidence of cancer and improve survival outcomes. However, the association between metformin use and the incidence and survival of endometrial cancer (EC) remains controversial. So, a meta-analysis was performed. An electronic search was conducted using PubMed, EMBASE, and Web of Science. The outcome measures were relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs) comparing the EC incidence and survival in patients treated with and without metformin. Eleven studies involving 766,926 participants were included in this study. In the pooled analysis of five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC risk among patients with diabetes (RR = 0.87, 95% CI: 0.80-0.95; p = 0.006). In the pooled analysis of six retrospective cohort studies evaluating the effect of metformin on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved the survival of EC patients (HR = 0.63, 95% CI: 0.45-0.87; p = 0.006). This study showed that metformin use was significantly associated with a decreased incidence of EC in diabetes and a favorable survival outcome of EC patients.

Circulating omentin-1 levels in women with polycystic ovary syndrome: a meta-analysis.

To investigate the association between circulating omentin-1 levels and polycystic ovary syndrome (PCOS) in women, a meta-analysis was performed. A systematic literature search using PubMed, Embase and Web of Science was carried out. Ten articles with 13 studies were included in this meta-analysis, which included a total of 1264 subjects (733 patients with PCOS and 531 controls). The pooled standard mean difference (SMD) and 95% confidence interval (CI) were used to estimate the association between omentin-1 levels and PCOS. Circulating omentin-1 levels were lower in PCOS with an SMD (95% CI) of -0.67 (-0.91, -0.43) and p = 0.000 (random-effects). However, significant heterogeneity was detected across studies (I2=73.6% and p = 0.000). The subgroup analysis suggested that omentin-1 levels in PCOS patients were associated with HOMA-IR ratio. Meta-regression analysis indicated region was the main source of heterogeneity (p = 0.048). The results of this meta-analysis suggested that circulating omentin-1 levels are significantly lower in women with PCOS compared with controls, which indicated that omentin-1 may play a role in the pathologic processes of PCOS.

Ultrasound elastographic findings of mammary fibromatosis.

Mammary fibromatosis is an uncommon, benign tumor of the breast. It is locally aggressive and has a high rate of recurrence. Its clinical presentation and imaging results always call for suspicion of malignancy. Here we describe a case of mammary fibromatosis with clinical manifestation, radiographic and pathologic results, and imaging findings from ultrasound elastography.

Girdin correlated with autophagy in invasive ductal breast carcinomas.

AIMS AND BACKGROUND: Increasing evidence claims that autophagy is essential for breast cancer progression. Girdin was found highly expressed in breast cancers. It has been reported that Girdin attenuates autophagy in HeLa cells. We explored the relationship between Girdin expression and autophagic patterns in breast cancer. METHODS AND STUDY DESIGN: In the study, Girdin expression and autophagic activity were investigated in a series of 99 invasive ductal breast carcinomas after immunohistochemical staining for the autophagy-associated proteins LC3-II and Girdin. RESULTS: The level of Girdin expression negatively correlated with LC3-II level, which represents autophagic activity (r = -0.289), and positively correlated with lymph node metastasis (r = 0.472). Girdin level was found no different in the "diffuse cytoplasmic" and "stone-like" patterns of LC3-II. CONCLUSIONS: Up-regulated autophagy was negatively associated with Girdin level. There was a significant correlation between Girdin expression and lymph nodes metastasis in invasive ductal breast carcinoma.

Decreased serum hepcidin concentration correlates with brain iron deposition in patients with HBV-related cirrhosis.

PURPOSE: Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level. METHODS: Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters. RESULTS: Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients. CONCLUSIONS: Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.

[Clinicopathologic features and prognostic factors of malignant phyllodes tumors].

OBJECTIVE: To study the clinicopathologic features of malignant phyllodes tumors (PT) by histopathologic analyses, immunohistochemical profiling and DNA content assay, and evaluation of the clinical outcome. METHODS: Ten patients with malignant PT from 1999 to 2013 who were treated by surgery were enrolled in this study. The morphologic characteristics were studied under light microscope, standard two-step EnVision method of immunohistochemical staining was used to assess the expression of CK5/6, CKpan, 34ß E12, desmin, p63, ER-α, PR, Ki-67, CD34, SMA, p53, p16, bcl-2 and CD117 in the tumors. The corresponding paraffin blocks were also used for flow cytometric DNA content assay. These data were correlated with the follow-up results. RESULTS: The median age of onset was 46.5 years old. The mean tumor size was 7.4 cm (2.0-25.0 cm). At the end of the follow-up period (22 to 125 months), there were tumor recurrences in 3/8 patients and the median time of recurrence was 24 months. Metastasis occurred in 3/8 patients who all died of the tumors. PT had heterogeneous histology, with stromal overgrowth with leaf-like projections, periductal stromal overgrowth, and most commonly, diffuse stromal overgrowth with sarcomatous differentiation. The mean positive index of Ki-67 was 11.4%. The stromal tumor cells were positive for CD34, SMA, p53, p16, and bcl-2 in 3/10, 9/10, 6/10, 8/10, and 4/10 cases, respectively. CD117,ER-α and PR were negative. Interpretable DNA histograms were obtained in nine cases with triploidy in two cases. CONCLUSIONS: The diagnosis of malignant PT should be considered based on the diversity of growth patterns and heterogeneous histology.Ki-67 and CD34 are valuable diagnostic and prognostic factors in patients with malignant PT. Tumors with diffuse stromal overgrowth, heterologous elements, Ki-67 ≥ 20% or aneuploidy are more likely to metastasize.

Epithelial mesenchymal transition is required for acquisition of anoikis resistance and metastatic potential in adenoid cystic carcinoma.

Human adenoid cystic carcinoma (ACC) is characterized by diffused invasion of the tumor into adjacent organs and early distant metastasis. Anoikis resistance and epithelial mesenchymal transition (EMT) are considered prerequisites for cancer cells to metastasize. Exploring the relationship between these processes and their underlying mechanism of action is a promising way to better understand ACC tumors. We initially established anoikis-resistant sublines of ACC cells; the variant cells revealed a mesenchymal phenotype through Slug-mediated EMT-like transformation and displayed enhanced metastatic potential both in vitro and in vivo. Suppression of EMT by knockdown of Slug significantly impaired anoikis resistance, migration, and invasion of the variant cells. With overexpression of Slug and Twist, we determined that induction of EMT in normal ACC cells could prevent anoikis, albeit partially. These findings strongly suggest that EMT is indispensable in anoikis resistance, at least in ACC cells. Furthermore, we found that the EGFR/PI3K/Akt pathway acts as the common regulator for EMT-like transformation and anoikis resistance, as confirmed by their specific inhibitors. Gefitinib and LY294003 restored the sensibilities of anoikis-resistant cells to anoikis and simultaneously impaired their metastatic potential. In addition, the results from our in vivo model of metastasis suggest that pretreatment with gefitinib promotes mouse survival by alleviating pulmonary metastasis. Most importantly, immunohistochemistry of human ACC specimens showed a correlation between the overexpression of Slug and EGFR staining. This study has demonstrated that Slug-mediated EMT-like transformation is required by human ACC cells to achieve anoikis resistance and their metastatic potential. Targeting the EGFR/PI3K/Akt pathway holds potential as a preventive strategy against distant metastasis of ACC.

Prenatal diagnosis of anhidrotic ectodermal dysplasia with unconventional loci abnormalities: a case report.

Anhidrotic ectodermal dysplasia (EDA) is a relatively rare congenital hereditary disease. Because of a reduced number of sweat glands, patients are unable to perspire and consequently suffer from hyperthermia and infection. This is a potential cause of death in childhood. Domestic prenatal diagnosis methods focus on genetic diagnosis. But for some conditions, because of the uncertain molecular pathology, we need other methods to assist to in prenatal diagnosis. Here, we report one case of a new mutation locus which may be associated with EDA and the prenatal diagnosis of EDA by fetal skin biopsy under fetoscopy in mid pregnancy, combined with a review of the literature.

Pediatric parotid tumors: clinical review of 24 cases in a Chinese population.

OBJECTIVE: To evaluate the incidence, types, and treatment outcomes of pediatric parotid tumors in Chinese population. METHODS: Pediatric salivary gland tumors treated at Stomatolgy Hospital, of Wuhan University, from 1990 to 2010, were analyzed retrospectively. RESULTS: One hundred and two patients 18 years old or younger were diagnosed as parotid mass, of which 24 (23.5%) were parotid tumors. Of these patients, 11 (45.8%) were benign and 13 (54.2%) malignant. Hemangioma was the most frequent no-epithelial tumor. The most common benign epithelial tumor was pleomorphic adenoma (63.6%), and the most common malignant epithelial tumor was mucoepidermoid carcinoma (38.5%), with both of them showing a female to male predominance. The most common treatment was parotidectomy (83.3%). CONCLUSIONS: Although pediatric parotid masses are unusual, they can represent a variety of pathological diagnoses, including malignancy. The intralesional injection can treat parotid hemangiomas in pediatric population effectively. Parotidectomy remains the mainstay treatment for both pediatric parotid gland benign and malignancies of epithelial cell origin. Adjuvant radiotherapy should be used judiciously in pediatric patients due to the higher risk of post-irradiation complications.

Clinical implications for girdin protein expression in breast cancer.

Girdin is highly expressed in breast carcinomas. Suppression of Girdin inhibited breast cancer cell migration. However, the clinical implications of Girdin as a marker are still unclear. Here we examined 80 breast cancer specimens using immunohistochemistry. Overall, positive Girdin staining was 41.25% in all of the cases. Girdin was strongly expressed in tumors of CerbB2-positive breast cancers (p < .05). Cases with both CerbB2- and Girdin-positive expression had a higher histological grade than the others. These findings indicated the closed relationship between breast cancer progression and Girdin expression. Girdin together with CerbB2 might be a new potential marker for breast cancers.

[Detection of human epidermal growth factor receptor 2 gene in invasive breast cancer by fluorescence in situ hybridization and research of its association with tumor characteristics].

OBJECTIVE: To investigate the concordance of detecting human epidermal growth factor receptor 2 (HER-2) status of patients with invasive breast cancer by fluorescence in situ hybridization (FISH) for gene amplification and immunohistochemistry (IHC) for protein overexpression and to evaluate the association between tumour characteristics and HER-2 gene amplification. METHODS: The HER-2 status was evaluated in 41 invasive ductal breast carcinomas by both FISH and IHC. The associations between HER-2 gene amplification and other clinicopathological factors, tumour grade, estrogen receptor (ER), tumor emboli, lymph node status, were evaluated using the chi-square test. RESULTS: HER-2 amplifications by FISH were seen in 15 patients, including 8 IHC+++ patients (88.89%, 8/9 of all+++ cases), 6 IHC++ patients (42.68%, 6/14 of all++ cases), 1 IHC+ patient (8.33%, 1/12 of all+ cases) and none IHC negative patient (0%, 0/6 of all negative cases). ER negative or weak positive breast cancers were more often HER-2 FISH positive than ER strong positive cancers (P=0.018). HER-2 amplifications were more often negative in tumor emboli negative or lymph node negative patients than in tumor emboli positive or lymph node positive patients (P=0.000, P=0.025). There was no statistical difference in HER-2 gene amplification among different grades of tumors(P=0.095). CONCLUSION: HER-2 amplification in breast cancer can be determined by FISH accurately. ER is negatively associated with HER-2 amplification, whereas tumor emboli and lymph node status are positively associated with HER-2.

[Comparison of two different tissue decalcification methods for immunohistochemistry].

OBJECTIVE: To investigate the effects of 1% hydrochloric acid and 10% nitric acid on immunohistochemical staining for several antigens. METHODS: Fifteen cases of focally calcified soft tumors including three cases of thyroid papillary carcinoma, three of breast invasive ductal carcinoma, three of prostate cancer, three of colon adenocarcincoma and three of normal lymph nodes, were selected in this study, and so were nine cases of bone and bone marrow tissue from biopsy and autopsy. Tissue samples were divided into three groups. One group was each soaked into 10% nitric acid for 24, 42 and 48 h, another group was each incubated in 1% hydrochloric acid for 1, 2 and 3 h. The other group which was not treated with acid was regarded as control. Then immunohistochemical staining was conducted in these samples for antigens as follows: ER, PR and Ki-67 in breast invasive ductal carcinoma; TTF-1 in thyroid papillary carcinoma; 34ßE12 and P504s in prostate cancer; AE1/AE3, P504s and Ki-67 in colon adenocarcincoma; CD3, CD20 and Ki-67 in lymph nodes; CD3,CD20,CD68,CD235a,MPO,Ki-67,AE1/AE3 and TTF-1 in bone tissue. RESULTS: After the tissues decalcificated in both acid solutions for some time, the numbers of positive cells decreased and the intensity of immunostaining became weaker, which was proportionate to time. Bone tissue was less influenced than calcified soft tissue. Different antigens showed different sensitivity to the same acid treatment. TTF-1 and Ki-67 were the two most vulnerable antigens among them; while ER, CD3 and CD20 were the least influenced. The effects of decalcification on immunostaining of one antigen were the same in different tissues. CONCLUSION: In most cases, both hydrochloric acid and nitric acid decalcification can lower the sensitivity of immunohistochemical staining, but have different effects on different antigens. It is better to use 10% nitric acid for decalcification of relatively large bone tissue and to use 1% hydrochloric acid for bone marrow tissues and bone tissues containing much more soft tissue.

Prediction of recurrence risk in early breast cancer using human epidermal growth factor 2 and cyclin A2.

BACKGROUND: Human epidermal growth factor 2 (HER2) is one of the most important prediction factors, but only 25% - 30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular markers that could be used to predict prognosis and recurrence in HER2 negative patients. This study investigated correlations of cyclin A2 and HER2 levels with clinical outcomes in 281 patients with invasive breast cancer in order to identify whether cyclin A2 can serve as a prognostic factor in HER2 negative patients. METHODS: Immunohistochemical staining was used to detect cyclin A2 and HER2 expression in 281 patients. Cyclin A2 and HER2 gene amplifications were analyzed using gene analysis and RT-PCR in 12 patients. Risk and survival estimates were analyzed using Log-rank, Kaplan-Meier, and Cox regression analysis; cyclin A2 and HER2 consistency with survival were analyzed using Kappa analysis. RESULTS: Patients with higher cyclin A2 and HER2 expressions had significantly shorter disease-free survival periods (P = 0.047 and P = 0.05, respectively). Kappa analysis performed that cyclin A2 and HER2 showed a low Kappa index (kappa = 0.37), allowing us to conclude that cyclin A2 and HER2 detect different pathologies. Gene analysis and RT-PCR showed that cyclin A2 was upregulated in patients with early relapse; the average increase was 3.69 - 2.74 fold. CONCLUSIONS: Cyclin A2 and HER2 are associated with proliferation and high recurrence, particularly when combined. Cyclin A2 is easily detected by nuclear staining and might be a useful biomarker for recurrence risk in HER2 negative patients.

[Study on protective effect of grape procyanidins in radiation injury in radiation-contacted persons].

OBJECTIVE: To study the protective effect of Grape procyanidins (GPC) on radiation injury in radiation-contacted persons. METHODS: Sixty radiation-contacted persons were randomly divided into the experimental group and the control group and 15 radiation-uncontacted persons were selected as the normal group. The experimental group was given GPC (100 mg/day), while the control group was given the capsule of starch every day for 60 days. Vein blood samples were taken before and after the study and the total antioxidative capacity (T-AOC), Malondialdehyde (MDA), cell proliferation, expression levels of proliferative cell nuclear antigen (PCNA), Bcl-2 and Bax protein, WBC were measured. RESULTS: The WBC, T-AOC and cell proliferation rate of the experimental group were (5.62 +/- 0.40) 10(9)/L, (17.07 +/- 1.91) U/ml and 0.87 +/- 0.09 respectively, which were significantly higher than those of the control group. The MDA and Bax expression levels were (4.12 +/- 0.37) nmol/L and 28.06% +/- 5.79% respectively that were significantly lower than those of the control group. CONCLUSION: GPC should have protective effects on radiation injury of the radiation-contacted persons.

Cutaneous epithelioid angioleiomyoma with clear-cell change.

Epithelioid angioleiomyoma is rare in the skin and subcutis. We report here an unusual case of epithelioid angioleiomyoma with prominent clear-cell change. Smooth-muscle differentiation was confirmed by immunostains. The extensive clear-cell change in epithelial cells and the marked hyalinization and calcification made the histologic differential diagnosis challenging. Epithelioid angioleiomyoma shares some histologic characteristics with glomus tumors and seems to be an intermediate entity between angioleiomyomas and glomus tumors.