Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases.

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the ß-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3ßpS9 (GSK3ß activity inhibition through serine 9 phosphorylation at GSK3ß), p53 wild-type (p53WT), and p53 mutant (p53MT) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53WT, and p53MT and increase in GSK3ßpS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3ßpS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53WT, p53MT, and GSK3ßpS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3ßpS9, for older patients at elevated risk of CRC.

The Human TOR Signaling Regulator Is the Key Indicator of Liver Cancer Patients' Overall Survival: TIPRL/LC3/CD133/CD44 as Potential Biomarkers for Early Liver Cancers.

Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we stained tissues of human liver disease/cancer with antibodies against TIPRL/LC3/CD133/CD44/CD46, followed by confocal observation. The roles of TIPRL/LC3/CD133/CD44/CD46 in liver normal and cancer cell lines were determined by in vitro studies. We analyzed the prognostic and diagnostic potentials of TIPRL/LC3/CD133/CD44/CD46 using the receiver-operating characteristic curve, a Kaplan-Meier and uni-/multi-Cox analyses. TIPRL and LC3 were upregulated in tissues of HCCs and adult hepatocytes-derived liver diseases while downregulated in iCCA. Intriguingly, TIPRL levels were found to be critically associated with liver cancer patients' survivability, and TIPRL is the key player in liver cancer cell proliferation and viability via stemness and self-renewal induction. Furthermore, we demonstrate that TIPRL/LC3/CD133 have shown prominent efficiency for diagnosing patients with grade 1 iCCA. TIPRL/LC3/CD133/CD44 have also provided excellent potential for prognosticating patients with grade 1 iCCA and grade 1 HCCs, together with demonstrating that TIPRL/LC3/CD133/CD44 are, either individually or in conjunction, potential biomarkers for early liver cancer.

Natural course of fat necrosis after breast reconstruction: a 10-year follow-up study.

BACKGROUND: Although fat necrosis is a minor postoperative complication after breast reconstruction, occasionally it mimics to tumor recurrence in patients with breast cancer. Therefore, the surgeon should distinguish between benign fat necrosis and true local recurrence. The authors evaluated the clinical characteristics of fat necrosis after breast reconstruction and investigated the natural course of fat necrosis. METHODS: Between 2007 and 2013, a total of 362 patients underwent breast reconstruction after partial or total mastectomy for breast cancer in Kyungpook National University Hospital. Clinicopathologic characteristics and the occurrence of fat necrosis were assessed during surveillance for 10 years of mean follow-up period. RESULTS: There were 42 cases (11.6%) of fat necrosis after breast reconstruction with partial or total mastectomy which were confirmed by needle or excision biopsy. The fat necrosis was resolved after a mean period of 45.9 months (SD, ± 42.1) and 26 cases (61.9%) of fat necrosis were almost completely resolved (less than 5 mm) during 10-year follow-up period. CONCLUSION: Based on the natural course of fat necrosis, the fat necrosis after breast reconstruction can be only monitored, if pathologic confirmation was done. More than half of the cases will be resolved within 2-3 years.

Reduction of Squalene Epoxidase by Cholesterol Accumulation Accelerates Colorectal Cancer Progression and Metastasis.

BACKGROUND & AIMS: Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is suggested as a proto-oncogene. Paradoxically, SQLE is degraded by excess cholesterol, and low SQLE is associated with aggressive colorectal cancer (CRC). Therefore, we studied the functional consequences of SQLE reduction in CRC progression. METHODS: Gene and protein expression data and clinical features of CRCs were obtained from public databases and 293 human tissues, analyzed by immunohistochemistry. In vitro studies showed underlying mechanisms of CRC progression mediated by SQLE reduction. Mice were fed a 2% high-cholesterol or a control diet before and after cecum implantation of SQLE genetic knockdown/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively. RESULTS: In vitro studies showed that SQLE reduction helped cancer cells overcome constraints by inducing the epithelial-mesenchymal transition required to generate cancer stem cells. Surprisingly, SQLE interacted with GSK3ß and p53. Active GSK3ß contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3ß/p53 complex, resulting in a metastatic phenotype. This was confirmed in a spontaneous CRC metastasis mice model, where SQLE reduction, by a high-cholesterol regimen or genetic knockdown, strikingly promoted CRC aggressiveness through the production of migratory cancer stem cells. CONCLUSIONS: We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the ß-catenin oncogenic pathway and deactivation of the p53 tumor suppressor pathway. Our findings provide new insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC aggressiveness and a prognostic biomarker.

Coiled-coil domain containing 50-V2 protein positively regulates neurite outgrowth.

The coiled-coil domain containing 50 (CCDC50) protein is a phosphotyrosine-dependent signalling protein stimulated by epidermal growth factor. It is highly expressed in neuronal cells in the central nervous system; however, the roles of CCDC50 in neuronal development are largely unknown. In this study, we showed that the depletion of CCDC50-V2 impeded the neuronal development process, including arbor formation, spine density development, and axonal outgrowth, in primary neurons. Mechanistic studies revealed that CCDC50-V2 positively regulated the nerve growth factor receptor, while it downregulated the epidermal growth factor receptor pathway. Importantly, JNK/c-Jun activation was found to be induced by the CCDC50-V2 overexpression, in which the interaction between CCDC50-V2 and JNK2 was also observed. Overall, the present study demonstrates a novel mechanism of CCDC50 function in neuronal development and provides new insight into the link between CCDC50 function and the aetiology of neurological disorders.

Pancreatic Hemangioma Suspected of Neuroendocrine Tumor.

Adult pancreatic hemangioma is an extremely rare disease, with only 22 cases reported since 1939. Pancreatic hemangioma has no specific symptoms, diagnostic imaging, or laboratory findings, making it difficult to be clinically suspected and diagnosed. The majority are confirmed after surgery. In this report, a 61-year-old woman presented with melena and showed multiple small hyper-vascular lesions in the pancreas. A pancreatic neuroendocrine tumor was suspected, and the patient underwent a distal pancreatectomy. The pathology examination and immunohistochemical study revealed a pancreatic hemangioma.

Molecular Profile and Clinicopathologic Features of Follicular Variant Papillary Thyroid Carcinoma.

The non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has an indolent clinical behavior. Recently, it was proposed that this tumor type should be reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). To characterize NIFTPs, we evaluated the molecular and clinicopathologic characteristics of each FVPTC subtype. This study enrolled 29 patients with FVPTC who underwent thyroidectomy between January 2007 and June 2017. They were classified as non-invasive encapsulated FVPTC (NIFTP, n = 10), invasive encapsulated FVPTC (n = 11), and infiltrative FVPTC (n = 8) by two independent pathologists. Genetic alterations were analyzed by targeted next-generation sequencing using formalin-fixed, paraffin-embedded tissue samples and the clinicopathologic characteristics were retrospectively reviewed. There was no difference in preoperative cytologic classification between NIFTPs and invasive encapsulated FVPTCs, whereas infiltrative FVPTC was more likely to be Bethesda class VI than the encapsulated type (50% versus 9.5%; P = 0.033). Lymph node metastasis was not found in NIFTPs. There was no BRAFV600E mutation in NIFTPs, whereas one of 11 invasive encapsulated FVPTCs and three of 8 infiltrative FVPTCs harbored BRAFV600E. RAS mutations were frequently detected in encapsulated FVPTCs (5 of 10 NIFTPs and 4 of 11 invasive encapsulated FVPTCs) but were only detected in one case of the infiltrative type. There were no differences in molecular or clinicopathologic profiles between non-invasive and invasive encapsulated FVPTCs, except for lymph node metastasis and the presence of BRAFV600E. NIFTP has favorable pathologic characteristics with a high frequency of RAS mutations.

TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.

Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.

The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer.

Studies have reported dysregulation of TIPRL, LC3 and CD133 in liver cancer tissues. However, their respective relationships to liver cancer and roles as biomarkers for prognosis and diagnosis of liver cancer have never been studied. Here we report that the level of TIPRL is significantly correlated with levels of LC3 (Spearman r = 0.9) and CD133 (r = 0.7) in liver cancer tissues. We observed significant upregulations of TIPRL, LC3 and CD133 in hepatocellular carcinomas (HCCs) compared with adjacent normal tissues. Importantly, TIPRL, tested among additional variables, showed a significant impact on the prognosis of HCC patients. TIPRL knockdown significantly reduced expressions of LC3, CD133, stemness-related genes, as well as viability and stemness of liver cancer cell-lines, which were promoted by ectopic TIPRL expression. Either alone or as a combination, TIPRL, LC3 and CD133 showed significant values of area under the curve (AUC) and sensitivity/specificity in early liver cancer tissues. Furthermore, the statistical association and the diagnostic efficacies of TIPRL, LC3 and CD133 in HCC tissues were confirmed in a different IHC cohort. This data demonstrates that the complex involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness can together or individually serve as potential biomarkers for the early detection of liver cancer.

A liver-specific gene expression panel predicts the differentiation status of in vitro hepatocyte models.

Alternative cell sources, such as three-dimensional organoids and induced pluripotent stem cell-derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell-based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end-stage liver disease. Differentiated liver cells and three-dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver-specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver-specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a "percentage." We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of in vivo liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three-dimensional cultured HepaRG cells and human pluripotent stem cell-derived hepatocyte-like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver-specific markers were detected. CONCLUSION: Our study describes a quantitative and predictive model for differentiated samples, particularly liver-specific cells or organoids; and this model can be further expanded to various tissue-specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of in vitro liver models. (Hepatology 2017;66:1662-1674).

Novel indazole-based small compounds enhance TRAIL-induced apoptosis by inhibiting the MKK7-TIPRL interaction in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers. We first identified the hit compound, TRT-0002, from a chemical library of 6,000 compounds using a previously developed high-throughput enzyme-linked immunosorbent assay (ELISA) screening system, which was based on the interaction of mitogen-activated protein kinase kinase 7 (MKK7) and TOR signaling pathway regulator-like (TIPRL) proteins and a cell viability assay. To increase the efficacy of this TRAIL sensitizer, we synthesized 280 analogs of TRT-0002 and finally identified two lead compounds (TRT-0029 and TRT-0173). Co-treating cultured Huh7 cells with either TRT-0029 or TRT-0173 and TRAIL resulted in TRAIL-induced apoptosis due to the inhibition of the MKK7-TIPRL interaction and subsequent phosphorylation of MKK7 and c-Jun N-terminal kinase (JNK). In vivo, injection of these compounds and TRAIL into HCC xenograft tumors resulted in tumor regression. Taken together, our results suggest that the identified lead compounds serve as TRAIL sensitizers and represent a novel strategy to overcome TRAIL resistance in HCC.

Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis.

Tumor metastasis is the leading cause of cancer death. In the metastatic process, EMT is a unique phenotypic change that plays an important role in cell invasion and changes in cell morphology. Despite the clinical significance, the mechanism underlying tumor metastasis is still poorly understood. Here we report a novel mechanism by which secreted plasma glutamate carboxypeptidase(PGCP) negatively involves Wnt/ß-catenin signaling by DKK4 regulation in liver cancer metastasis. Pathway analysis of the RNA sequencing data showed that PGCP knockdown in liver cancer cell lines enriched the functions of cell migration, motility and mesenchymal cell differentiation. Depletion of PGCP promoted cell migration and invasion via activation of Wnt/ß-catenin signaling pathway components such as phospho-LRP6 and ß-catenin. Also, addition of DKK4 antagonized the Wnt/ß-catenin signaling cascade in a thyroxine (T4)-dependent manner. In an in vivo study, metastatic nodules were observed in the lungs of the mice after injection of shPGCP stable cell lines. Our findings suggest that PGCP negatively associates with Wnt/ß-catenin signaling during metastasis. Targeting this regulation may represent a novel and effective therapeutic option for liver cancer by preventing metastatic activity of primary tumor cells.

Expression of FOXM1 and related proteins in breast cancer molecular subtypes.

Forkhead box (FOX) proteins constitute an extended family of transcriptional regulators. FOXM1 is ubiquitously expressed in cells undergoing proliferation, and overexpression of FOXM1 is associated with poor prognosis in various malignant tumours. FOXM1 and FOXO3a are often transcriptionally antagonistic. FOXO3a plays a critical tumour-suppressive role in breast cancer. FOXO activity is modulated by its acetylation status, which is regulated by class III histone deacetylases (sirtuins; also known as SIRTs). This study evaluated the role of FOX proteins and their regulators in each molecular subtype of breast cancer. Immunohistochemical expressions of FOXM1, FOXO3a, SIRT1 and SIRT6 were evaluated in tissue microarray blocks containing 688 consecutive breast cancer samples. Mean expression levels were used to categorize tumours according to the expression of each protein (high or low). High expression of FOXM1 was significantly correlated with high SIRT1 and SIRT6 expression, higher histologic grade and triple-negative breast cancer (TNBC). High expression of nuclear FOXO3a and nuclear SIRT1 was correlated with a lower histologic grade and the hormone receptor-positive/HER2-negative subtype. In survival analysis, FOXM1 was an independent adverse prognostic factor for disease-free and overall survival in the hormone receptor-positive/HER2-negative subtype but not in the HER2-positive subtype or TNBC. In conclusion, although high FOXM1 expression was noted in the TNBC subtype, it had no prognostic impact in TNBC. However, it had prognostic significance in the hormone receptor-positive/HER2-negative subtype.

Novel TRAIL sensitizer Taraxacum officinale F.H. Wigg enhances TRAIL-induced apoptosis in Huh7 cells.

TRAIL (TNF-related apoptosis inducing ligand) is a promising anti-cancer drug target that selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL-induced apoptosis. Therefore, reversing TRAIL resistance is an important step for the development of effective TRAIL-based anti-cancer therapies. We previously reported that knockdown of the TOR signaling pathway regulator-like (TIPRL) protein caused TRAIL-induced apoptosis by activation of the MKK7-c-Jun N-terminal Kinase (JNK) pathway through disruption of the MKK7-TIPRL interaction. Here, we identified Taraxacum officinale F.H. Wigg (TO) as a novel TRAIL sensitizer from a set of 500 natural products using an ELISA system and validated its activity by GST pull-down analysis. Furthermore, combination treatment of Huh7 cells with TRAIL and TO resulted in TRAIL-induced apoptosis mediated through inhibition of the MKK7-TIPRL interaction and subsequent activation of MKK7-JNK phosphorylation. Interestingly, HPLC analysis identified chicoric acid as a major component of the TO extract, and combination treatment with chicoric acid and TRAIL induced TRAIL-induced cell apoptosis via JNK activation due to inhibition of the MKK7-TIPRL interaction. Our results suggest that TO plays an important role in TRAIL-induced apoptosis, and further functional studies are warranted to confirm the importance of TO as a novel TRAIL sensitizer for cancer therapy. © 2015 Wiley Periodicals, Inc.

Direct regulation of E-cadherin by targeted histone methylation of TALE-SET fusion protein in cancer cells.

TALE-nuclease chimeras (TALENs) can bind to and cleave specific genomic loci and, are used to engineer gene knockouts and additions. Recently, instead of using the FokI domain, epigenetically active domains, such as TET1 and LSD1, have been combined with TAL effector domains to regulate targeted gene expression via DNA and histone demethylation. However, studies of histone methylation in the TALE system have not been performed. Therefore, in this study, we established a novel targeted regulation system with a TAL effector domain and a histone methylation domain. To construct a TALE-methylation fusion protein, we combined a TAL effector domain containing an E-Box region to act as a Snail binding site and the SET domain of EHMT 2 to allow for histone methylation. The constructed TALE-SET module (TSET) repressed the expression of E-cadherin via by increasing H3K9 dimethylation. Moreover, the cells that overexpressed TSET showed increased cell migration and invasion. This is the first phenotype-based study of targeted histone methylation by the TALE module, and this new system can be applied in new cancer therapies to reduce side effects.

Overexpression of cytokeratin 17 is associated with the development of papillary thyroid carcinoma and the presence of lymph node metastasis.

Cytokeratin 17 (CK17), a basal/myoepithelial cell keratin, appears to play an important role in the progression of several human malignancies. Increased CK17 expression has previously described in cases of papillary thyroid carcinoma (PTC). However, no studies to date have investigated the clinical significance of CK17 expression in patients with PTC. The aim of this study was to compare the expression of CK17 in patients with PTC with that observed in normal thyroid tissue and benign thyroid lesions, and to examine the relationship between CK17 expression and clinicopathologic characteristics of patients with PTC. CK17 protein expression was evaluated by immunohistochemistry on tissue microarrays containing thyroid tissue samples from 108 PTCs, 16 nodular goiters, and 81 healthy controls. Sixty-five of the 108 (60.2%) PTC tissue samples exhibited positive CK17 expression, whereas all nodular goiters and normal thyroid tissue samples showed a complete absence of CK17 immunoreactivity. The difference in frequency of CK17 positivity between PTC (65/108, 60.2%), normal thyroid tissue (0/81, 0.0%), and benign thyroid lesions (0/16, 0.0%) was statistically significant (P<0.001). Positive CK17 expression in PTC was significantly associated with the presence of lymph node metastasis (P=0.024) and higher pN stage (P=0.028). Expression of CK17 is significantly increased in cases of PTC compared to normal tissue and benign thyroid lesions, and CK17 overexpression is associated with the presence of lymph node metastasis in patients with PTC. These findings suggest that CK17 is involved in the development and metastasis of PTC.

Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes.

The prognostic significance of tumor-infiltrating lymphocytes and immune signals has been described previously in triple-negative breast cancer (TNBC). Furthermore, recent studies have shown that immunologic parameters are relevant for the response to neoadjuvant chemotherapy (NAC) in breast cancer as well as for outcomes after adjuvant chemotherapy. However, immune signals are variable, and which signals are important is largely unknown. We, therefore, evaluated the expression of immune-related genes in TNBC treated with NAC. We retrospectively evaluated biopsy tissue from 55 patients with primary TNBC treated with NAC (anthracycline, cyclophosphamide, and docetaxel) against the NanoString nCounter GX Human Immunology Panel (579 immune-related genes). Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, cytokines related to T helper cell type 1 (Th1), and B cell markers was associated with a pathologic complete response (pCR). Higher expression of NFKB1, MAPK1, TRAF1, CXCL13, GZMK, and IL7R was significantly associated with pCR, higher Miller-Payne grade, and lower residual cancer burden class. Expression of NFKB1, TRAF1, and CXCL13genes, in particular, was significantly correlated with a longer disease-free survival rate. Conversely, patients those who failed to achieve a pCR showed increased expression of genes related to neutrophils. Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, Th1-related cytokines, and B cell markers is correlated with pCR and survival in TNBC patients treated with NAC. Our results suggest that the activation status of neutrophils may provide additional predictive information for TNBC patients treated with NAC.

IFT46 plays an essential role in cilia development.

Cilia are microtubule-based structures that project into the extracellular space. Ciliary defects are associated with several human diseases, including polycystic kidney disease, primary ciliary dyskinesia, left-right axis patterning, hydrocephalus and retinal degeneration. However, the genetic and cellular biological control of ciliogenesis remains poorly understood. The IFT46 is one of the highly conserved intraflagellar transport complex B proteins. In zebrafish, ift46 is expressed in various ciliated tissues such as Kupffer׳s vesicle, pronephric ducts, ears and spinal cord. We show that ift46 is localized to the basal body. Knockdown of ift46 gene results in multiple phenotypes associated with various ciliopathies including kidney cysts, pericardial edema and ventral axis curvature. In ift46 morphants, cilia in kidney and spinal canal are shortened and abnormal. Similar ciliary defects are observed in otic vesicles, lateral line hair cells, olfactory pits, but not in Kupffer׳s vesicle. To explore the functions of Ift46 during mouse development, we have generated Ift46 knock-out mice. The Ift46 mutants have developmental defects in brain, neural tube and heart. In particular Ift46(-/-) homozygotes displays randomization of the embryo heart looping, which is a hallmark of defective left-right (L/R) axis patterning. Taken together, our results demonstrated that IFT46 has an essential role in vertebrate ciliary development.

Correlations between molecular subtypes and pathologic response patterns of breast cancers after neoadjuvant chemotherapy.

BACKGROUND: The relationship between the pathologic response patterns after neoadjuvant chemotherapy (NAC) and specific subtypes of breast cancer is unclear. METHODS: This study retrospectively analyzed 351 tumors from 348 women with breast cancer who received anthracycline and taxane-based NAC and subsequent surgery. Various histopathologic factors were assessed in the pretreatment biopsy and surgery specimens based on molecular subtypes defined by immunohistochemistry. RESULTS: The tumors without a pathologic complete response in each subtype retained their morphologic features after NAC. Lymphocytic infiltration was higher in the hormone receptor-negative (HR-) tumors than in the HR+ tumors. The HR- tumors showed more necrosis and histiocytic infiltration in the tumor bed than the HR+ tumors. The overall (including in situ carcinoma) and invasive pathologic cancer sizes were similar for the triple-negative tumors only. Although all the subtypes showed significantly reduced tumor size after NAC, the difference between the pre-NAC magnetic resonance imaging (MRI) tumor size and the overall pathologic cancer size was significantly smaller for the HR+/human epidermal growth factor receptor 2-negative (HER2-) subgroup than for the triple-negative subgroup. The triple-negative tumors showed the highest correlation between post-NAC tumor size measured by MRI and overall or invasive pathologic tumor size. CONCLUSION: The molecular subtypes of breast cancer have characteristic pathologic patterns of response to NAC.