Search

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Immune checkpoint blockade (ICB) has been explored as a therapeutic strategy to recover the antitumor immune activities against endometrial cancer (EC) escaping from immune surveillance. Increasing evidence has indicated that microsatellite instability (MSI) is a promising biomarker to stratify patients for the ICB therapy. However, even in patients with MSI-High (MSI-H) endometrial cancers, PD-L1 inhibitors, avelumab, and durvalumab have shown only 27% of response rates. Therefore, there is an urgent need to discover new biomarkers for a predictive response to ICB therapy. In this study, we demonstrated that the immune cytolytic activity (CYT) index was significantly correlated with the development and response to immunotherapy in EC. The data showed that higher CYT was significantly associated with better clinical outcome, more antitumor infiltrating immune cells, fewer somatic copy number alterations, but a higher TMB (Tumor mutational burden) status. Furthermore, CYT-high EC was notably relevant to the high expression of various immune checkpoint molecules and showed more effective responses to ICB treatment. Taken together, this study provided new insights into the connection between diverse genetic events and the immune microenvironment in EC and indicated that the CYT status might be a promising biomarker to stratify patients with EC for ICB therapy.

PDF file - 596K, Table S1: Predicted GSK3b phosphorylation sites on SMO. TableS2: Predicted GSK3b phosphorylation sites on SMO. FIG S1: Generation of cell lines resistant to increasing concentration of tamoxifen. FIG S2: Mammosphere formation assay with cells resistant to increasing concentration of tamoxifen. FIG S3: Effect of Gli1 depletion on OHTR and T47D cells. FIG S4: Regulation of GLI1 by PI3k/Akt pathway.

The efficacy of immune checkpoint inhibitors (ICIs) on KRAS-mutant advanced non-small cell lung cancer (NSCLC) remains controversial. This retrospective study compared the effects of ICIs treatment and chemotherapy on the prognosis of patients with KRAS-mutant advanced NSCLC and different mutant subtypes in the real world. The study included 95 patients with KRAS-mutant advanced NSCLC. Patients treated with first-line ICIs plus platinum-containing chemotherapy had better progression-free survival (PFS) (7.4 vs 4.5 months, P = 0.035) and overall survival (OS) (24.1 vs 13.2 months, P = 0.007) than those receiving platinum-containing chemotherapy alone, and second-line ICI monotherapy was associated with better PFS (4.8 vs 3.0 months, P = 0.043) and OS (18.0 vs 13.8 months, P = 0.013) than chemotherapy monotherapy. There was no significant difference in PFS (5.267 vs 6.734 months, P = 0.969) and OS (19.933 vs 20.933 months, P = 0.808) between patients with KRAS-mutant and KRAS-wild-type NSCLC treated with ICIs or between KRAS G12C and KRAS non-G12C patients (PFS: 8.1 vs 4.8 months, P = 0.307; OS: 21.3 vs 21.8 months, P = 0.434). In summary, patients with advanced NSCLC with KRAS mutations can benefit from ICIs, but no difference between KRAS mutant subtypes was observed.

Human epidermal growth factor receptor 2 (HER2) possesses tyrosine kinase activity and participates in cell growth, differentiation and migration, and survival. Its alterations, mainly including mutations, amplifications, and overexpression are associated with poor prognosis and are one of the major drivers in non-small cell lung cancer (NSCLC). Several clinical trials had been investigating on the treatments of HER2-altered NSCLC, including conventional chemotherapy, programmed death 1 (PD-1) inhibitors, tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), however, the results were either disappointing or encouraging, but inconsistent. Trastuzumab deruxtecan (T-DXd) was recently approved by the Food and Drug Administration as the first targeted agent for treating HER2-mutant NSCLC. Effective screening of patients is the key to the clinical application of HER2-targeted agents such as TKIs and ADCs. Various testing methods are nowadays available, including polymerase chain reaction (PCR), next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), etc. Each method has its pros and cons and should be reasonably assigned to appropriate patients for diagnosis and guiding treatment decisions. To help standardize the clinical workflow, our expert group reached a consensus on the clinical management of HER2-altered NSCLC, focusing on the diagnosis and treatment strategies.

Background Triple-negative breast cancer (TNBC) is the most heterogenous and aggressive subtype of breast cancer. Chemotherapy remains the standard treatment option for patients with TNBC owing to the unavailability of acceptable targets and biomarkers in clinical practice. Novel biomarkers and targets for patient stratification and treatment of TNBC are urgently needed. In this study, we aimed to identify novel biomarkers and therapeutic targets using RNA sequencing (RNA-seq) and data mining using data from public databases. Methods RNA-sequencing (RNA-Seq) was performed to detect the different gene expression patterns in the human TNBC cell line HS578T treated with docetaxel or doxorubicin. Raw data were analyzed using the R package “edgeR” to identify the profile of differentially expressed genes (DEGs) and functionally annotated through R package “clusterProfiler.” The prognostic and predictive value of DNA damage-inducible transcript 4 gene (DDIT4) expression in patients with TNBC was further studied using published online data resources, including TIMER, UALCAN, and Kaplan-Meier Plotter. LinkedOmics and GeneMANIA were used to investigate the genes and functional networks related to DDIT4. GSCALite was used to analyze the pathway activities of DDIT4 and its hub genes. Results Through the integrative analyses of RNA-Seq data and public datasets, we observed the overexpression of DDIT4 in TNBC tissues(pppppConclusion In this study, we found that DDIT4 expression is associated with the progression, therapeutic efficacy, and immune microenvironment of patients with TNBC, and DDIT4 would be as a potential prognostic biomarker and therapeutic target. These findings will help to identify potential new molecular targets and improve therapeutic strategies against TNBC.

Background Lymphocyte-specific protein tyrosine kinase (LCK), an encoded Src family protein tyrosine kinase, performs a pivotal molecular signaling role in the selection and maturation processes during T-cell development. Although aberrant LCK expression is known to have a significant association with carcinogenesis, the underlying role of LCK in breast cancer (BC) is still obscure. Methods An analysis of the levels of LCK mRNA expression in BC was performed, and the value of LCK expression for predicting the prognosis of patients with BC was studied using various online data resources, which included Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and UALCAN. The web-based NetworkAnalyst tool was utilized to investigate the functional network of differentially expressed LCK. LinkedOmics was employed to identify the genes with which LCK has correlations in BC, together with the kinases, microRNAs, and transcription factors (TFs) potentially targeted by LCK in BC. The expression levels of LCK and its significantly correlated genes in BC were investigated with the Human Protein Atlas (HPA). Results We observed a significant difference in the level of LCK mRNA expression between BC patients and healthy individuals, and a higher LCK expression was associated with poor overall survival (OS). The functional enrichment results revealed that the differential expression of LCK was mainly involved in the regulation of immune response and inflammatory response in BC. The expression of significantly related genes, such as inducible T-cell kinase (ITK), CD5, CD96, CD247, SH2 domain containing 1A (SH2D1A), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CD), Src-like-adaptor 2 (SLA2), and interleukin 2 receptor (IL2RG), was associated with poor OS in patients with BC. Regulatory network analysis found that LCK regulated immune cells, cancer progression, apoptosis, and cell cycle signal transduction through cancer-related kinases (ITK and MAPK3), miRNAs (miR-345 and miR-524), and TFs (AP1, SRF, and E2F1). Conclusions This study presents new perspectives on the differential expression and prognostic value of LCK in BC. Our observations will provide a basis for further study on the oncogenic and regulatory roles of LCK in BC.

Renyu Zhou,1 Xiaoxi Zhu,2 Yulong Peng,1 Lijuan Zhong,1 Lilin Peng,1 Bo Yang,1 Yuhua Meng,3 Xuanzhao Chen,4 Yuanzhi Lu1,4 1Department of Pathology, First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 2Department of Oncology, First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 3Department of Pathology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, 528300, People’s Republic of China; 4The Center of Pathological Diagnosis and Research, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524023, People’s Republic of ChinaCorrespondence: Yuanzhi Lu, Tel +86-20 38688984, Email yuanzhi.lu@jnu.edu.cnIntroduction: Amplification of the 11q13.3 locus has been observed in various tumors. This study sought to determine the correlation of gene amplification at the 11q13.3 locus with the immune status and survival of breast cancer.Methods: Amplification of the 11q13.3 locus was characterized by analyzing a publicly available database from the cBioPortal platform (TCGA). The correlation of amplified genes with immune cell infiltration in breast cancer was further analyzed using the TIMER2.0 platform. Immunohistochemical staining was used to determine the expression levels of Cyclin D1 (CCND1), Fas-associated death domain (FADD) and P53 in 156 clinical breast cancer samples.Results: This study revealed that amplification of the 11q13.3 amplicon in breast cancer is likely more frequently detected in luminal B breast cancer. Moreover, high expression or amplification of CCND1, fibroblast growth factor 3 (FGF3), fibroblast growth factor 4 (FGF4), fibroblast growth factor 19 (FGF19) and FADD was inversely correlated with the abundance of CD4+ T cells and dendritic cell infiltration in breast cancer (P < 0.05). Data analysis also demonstrated that high expression of CCND1, FGF4 and FADD mRNA levels was closely correlated with shorter recurrence-free survival (RFS) in patients with breast cancer (P < 0.05). The results of immunohistochemical staining from clinical samples further confirmed that high expression of CCND1 and FADD was frequently detected in luminal B and high-grade breast cancer with shorter metastasis-free survival times (P < 0.05).Conclusion: This study demonstrated that coamplification of genes located on the 11q13.3 amplicon is frequently detected in luminal B subtype breast cancer and is closely associated with worse survival in patients with breast cancer. Moreover, coamplification of the CCND1-FGF locus might decrease antitumor immune activity in breast cancer, indicating that coamplification of the 11q13.3 amplicon is likely to be a key determinant of therapeutic resistance and accelerate the aggressive evolution of breast cancer.Keywords: breast cancer, chromosomal amplification, 11q13.3 amplicon, prognosis, immune microenvironment

Estrogen Receptor alpha (ERα) affects the morphology of tumors, which is closely related to the biomechanical properties and the cytoskeletal proteins. In recent years, researchers have found that biomechanical properties and cytoskeletal proteins are closely related to the occurrence and development of tumors and that biomechanical properties can be used as markers for tumor development and drug resistance. The relationship between ERα expression status and biomechanical properties, cytoskeletal proteins is not known. In this study, we found that tamoxifen-resistant breast cancer cells (MCF-7/TamR) altered cell morphology and lacked of ERα expression during the process of the Tamoxifen resistance induction. To determine whether this change was influenced by ERα expression, we transiently constructed another ERα depleted model with ERα siRNA (MCF-7/ERα siRNA) and used atomic force microscope (AFM) to detect morphological and biophysical changes. The results indicated that the roughness and Young's modulus of ERα expression depleted cells were significantly increased, accompanied by rearrangement of the cytoskeletal proteins (F-actin, FLNA, α-tubulin) and the cytoskeletal regulatory protein Rho (Rac1, CDC42) decreased. Our results have demonstrated that ERα depletion affects the biomechanical properties of breast cancer cells, which are related to cytoskeletal protein rearrangement and Rho protein decreased.

IntroductionResistance to second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), afatinib, is the most significant challenge in the clinical management of non-small cell lung cancer (NSCLC), and the underlying mechanisms remain unclear.MethodsGenomic signatures that may confer afatinib resistance in NSCLC were identified via data mining of public databases and integrative bioinformatic analyses. Furthermore, acquired afatinib-resistant lung adenocarcinoma cell lines (HCC827 AR) were established by long-term exposure under afatinib in vitro for stepwise escalation. The expression of baculovirus IAP repeat protein 5 (BIRC5) was detected by western blot, and cellular viability of HCC827 AR was determined by CCK8.ResultsThrough integrative bioinformatic analyses of public datasets, overexpression of baculovirus IAP repeat protein 5 (BIRC5) was identified in both afatinib-resistant NSCLC cells and tissues, and BIRC5 overexpression was positively correlated with lymph node metastasis as well as pathological stage in NSCLC. Furthermore, NSCLC patients with BIRC5 overexpression showed poor survival outcomes. Immune infiltration analysis suggested that BIRC5 expression was significantly inversely correlated with tumor-infiltrating cell numbers and immune biomarker expression in NSCLC. The functions of genes co-expressed with BIRC5 were mainly enriched in cell cycle mitotic phase transition, double-strand break repair, and negative regulation of the cell cycle process signaling pathway. In addition, overexpression of BIRC5 protein was detected in afatinib-resistant cells by western blot, while BIRC5-expressing cells treated with BIRC5 inhibitor, YM155, were sensitive to afatinib.ConclusionsIn this study, we showed that overexpression of BIRC5 resulted in resistance to afatinib in NSCLC and BIRC5-specific inhibitors may overcome the resistant phenotype, indicating that dysregulation of the apoptotic cell death pathway may be the key mechanism underlying TKI resistance in the development of NSCLC.

Background Drug resistance inevitably limits the efficacy of the second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib, and the underlying causes of this resistance have not been determined.Methods In this study, we demonstrated that baculovirus IAP repeat protein 5 (BIRC5) may confer afatinib resistance in non-small-cell lung cancer (NSCLC) via multiple mechanisms based on integrative bioinformatic analyses. Results Through bioinformatic analyses of microarray datasets, BIRC5 was overexpressed in both afatinib-resistant NSCLC cells and NSCLC tissues and was initially identified as a potential candidate gene causing poor survival in afatinib-resistant patients with NSCLC. The resistance function of BIRC5 in NSCLC was validated by performing protein/gene interactions and biological process annotation analyses and further validated by analyzing transcription factors targeting BIRC5 mRNA. Conclusions We applied our results to NSCLC and showed that BIRC5 was an important candidate gene for afatinib resistance.

Objective To summarize the roles of AKT-mTOR signaling in the regulation of the DNA damage response and PD-L1 expression in cancer cells, and propose a novel strategy of targeting AKT-mTOR signaling in combination with radioimmunotherapy in the era of cancer immunotherapy. Background Immunotherapy has greatly improved the clinical outcomes of many cancer patients and has changed the landscape of cancer patient management. However, only a small subgroup of cancer patients (~20-30%) benefit from immune checkpoint blockade-based immunotherapy. The current challenge is to find biomarkers to predict the response of patients to immunotherapy and strategies to sensitize patients to immunotherapy. Methods Search and review the literature which were published in PUBMED from 2000-2021 with the key words mTOR, AKT, drug resistance, DNA damage response, immunotherapy, PD-L1, DNA repair, radioimmunotherapy. Conclusions More than 50% of cancer patients receive radiotherapy during their course of treatment. Radiotherapy has been shown to reduce the growth of locally irradiated tumors as well as metastatic non-irradiated tumors (abscopal effects) by affecting systemic immunity. Consistently, immunotherapy has been demonstrated to enhance radiotherapy with more than one hundred clinical trials of radiation in combination with immunotherapy (radioimmunotherapy) across cancer types. Nevertheless, current available data have shown limited efficacy of trials testing radioimmunotherapy. AKT-mTOR signaling is a major tumor growth-promoting pathway and is upregulated in most cancers. AKT-mTOR signaling is activated by growth factors as well as genotoxic stresses including radiotherapy. Importantly, recent advances have shown that AKT-mTOR is one of the main signaling pathways that regulate DNA damage repair as well as PD-L1 levels in cancers. These recent advances clearly suggest a novel cancer therapy strategy by targeting AKT-mTOR signaling in combination with radioimmunotherapy.

The blueschist-bearing Aksu Group and the associated rocks in the Aksu–Wushi area play a crucial role in understanding Neoproterozoic tectonic evolution of the Tarim Craton. However, the age and tectonic setting of the Aksu Group, and its relationship with the Qiaoenbrak Formation, remain controversial. Previous studies were mainly focused on the well-known Aksu Group from the Aksu area, but little attention has been paid to the equivalent rocks from the Wushi area. In this paper, we present the first detrital zircon LA-ICP-MS U–Pb ages for the Aksu Group metasedimentary rocks from the Wushi area, and we also measure U–Pb ages for detrital zircons from the Qiaoenbrak Formation to figure out its affinity to the Aksu Group. Our data show that the protolith of the metasedimentary rocks of the Aksu Group from the Wushi area was deposited between ca. 790 and 761 Ma, which was earlier than that from the Aksu area (>ca. 750 Ma). The Qiaoenbrak Formation was deposited between ca. 780 and 744 Ma, probably contemporaneous with or earlier than the metasedimentary rocks of the Aksu Group. Geochemical data for the metasedimentary rocks of the Aksu Group from the Wushi area suggest that they were deposited in an arc-related setting. Combining the detrital zircon age spectra and geochemistry analyses, we propose that the sedimentary rocks of the Aksu Group and the Qiaoenbrak Formation were probably deposited in a similar tectonic setting related to an active continental margin in the northern margin of the Tarim Craton. The Aksu blueschists and the associated Neoproterozoic arc were probably related to the circum-Rodinia subduction system, rather than assembly of the Rodinia or Gondwana in the interior of the supercontinents.

The Fuchuan ophiolite belt in the eastern Jiangnan Orogen of South China provides important constraints on the tectonic setting and evolution of the Neoproterozoic suture zone between the Yangtze and Cathaysia blocks. Combined U Pb Hf isotopic and REE analysis of zircon from gabbroic and dioritic samples of the Shexian complex, located 10 km southwest of the main Fuchuan ophiolite body, indicate that the complex crystallized at ca. 870–860 Ma with a large variation of zircon e Hf (t) values from − 4.80 to + 13.30. Whole-rock geochemistry reveals that the magma mainly experienced fractionation of olivine, clinopyroxene and plagioclase and was partly affected by crustal contamination, which resulted in elevated Th/Nb, Th/La and La/Sm ratios, as well as the scattered e Hf (t) values. The most mafic and least contaminated sample shows MORB affinity and was probably formed by partial melting of a depleted subduction-metasomatized mantle wedge. Other samples exhibit arc-like signatures and were probably modified by both melt- and fluid-related subduction metasomatism. The emplacement of the Shexian complex corresponds to the time that subduction switched from a ca. 1000–880 Ma intra-oceanic island arc to a 870–830 Ma continental arc along the southeastern Yangtze Block. The sequence of igneous rocks associated with this continental arc resemble those preserved in forearc Tethyan ophiolites, with magma evolving from ca. 870–860 Ma MORB to ca. 860–850 Ma arc tholeiite and ca. 830 Ma boninite. Arc magmatism concluded with the final assembly of the Yangtze and Cathaysia blocks at 830–800 Ma.

The origin and tectonic setting of Precambrian sequences in the Central Asian Orogenic Belt (CAOB) have been debated due to a lack of high resolution geochronological data. Answering this question is essential for the understanding of the tectonic framework and Precambrian evolution of the blocks within the CAOB. Here we reported LA-ICP-MS detrital zircon U–Pb ages and in-situ Hf isotopic data for Neoproterozoic sedimentary cover in the northern Yili Block, an important component of the CAOB, in order to provide information on possible provenance and regional tectonic evolution. A total of 271 concordant U–Pb zircon ages from Neoproterozoic sedimentary cover in the northern Yili Block define three major age populations of 1900–1400 Ma, 1300–1150 Ma and 700–580 Ma, which are quite different from cratons and microcontinents involved in the CAOB. Although it is not completely consistent with the local basement ages, an autochthonous provenance interpretation is more suitable. Some zircon grains show significant old Hf model ages (TDMC; 3.9–2.4 Ga) and reveal continental crust as old as Paleoarchean probably existed. Continuous Mesoproterozoic zircon age populations exhibit large variations in the eHf(t) ratios, suggesting the long-time involvement of both reworked ancient crust and juvenile material. Similar Mesoproterozoic evolution pattern is identified in many continental terranes involved in the CAOB that surround the Tarim Craton. Based on our analysis and published research, we postulate that the northern Yili Block, together with Chinese Central Tianshan, Kyrgyz North Tianshan and some other microcontinents surrounding the Tarim Craton, once constituted the continental margin of the Tarim Craton in the Mesoproterozoic, formed by long-lived accretionary processes. Most of the late Neoproterozoic zircons exhibit significant positive eHf(t) ratios, suggesting the addition of juvenile crust. It is consistent with the tectonic event related to the East Africa Orogen in the Arabian-Nubian Shield and the northern Tarim Craton, indicating the affinity between them in Gondwana.

Neoproterozoic sedimentary units at the southeastern margin of the Yangtze Block, South China, record a complex geological history including development of the Jiangnan Orogen during assembly of the Yangtze and Cathaysia blocks and later episodes of glacial activity. The timing of these events is controversial, and we have used U–Pb–Hf compositions of detrital zircons from the Lantian type section to constrain their ages in southern Anhui Province, at the eastern end of the Jiangnan Orogen. This section comprises the Xikou Group below an angular unconformity, and the Xiuning Formation and overlying glacial Leigongwu Formation above the unconformity. Detrital zircons in all three units are dominated by 2.6–2.4 Ga, 2.1–1.9 Ga and 960–740 Ma age populations suggesting erosion from similar source regions, and an increasing proportion of older grains up through the sequence reflects a change in depositional environment from syn-collisional to extensional. Pre-Neoproterozoic zircon grains were derived from the Yangtze Block basement, much of which is now concealed by younger rocks, while the Neoproterozoic population was eroded from local igneous rocks in the Jiangnan Orogen. Zircon Hf isotope compositions indicate that 2.6–2.4 Ga source rocks were a mix of juvenile and reworked crust, while 2.1–1.9 Ga source rocks were dominated by reworked crust. Neoproterozoic sources show a switch from 960–860 Ma juvenile crust to 860–740 Ma juvenile and reworked crust, reflecting a transition in the Jiangnan Orogen from subduction to collision and extension. The youngest detrital grains in the Xikou Group and overlying Xiuning Formation indicate deposition after ca. 810 Ma and ca. 732 Ma, respectively, correlating closely with comparable sequences elsewhere in the Yangtze Block. This demonstrates that the unconformity in South Anhui is part of a regional erosion surface that formed more or less synchronously throughout the orogen at 830–800 Ma, consistent with it dating the end of collision between the Yangtze and Cathaysia blocks. The age of the overlying glacial Leigongwu Formation is difficult to constrain from detrital zircons because of a paucity of post-720 Ma source rocks, but our data suggest the Leigongwu diamictite in the Lantian section is a single Marinoan-age glacial unit deposited after 649 ± 13 Ma. It follows that a carbonate layer in the middle of the Leigongwu diamictite in the Lantian section most likely reflects later faulting, rather than two separate glacial sequences, although we cannot rule out the presence of both Sturtian and Marinoan diamictite elsewhere in South Anhui.

The Proterozoic is the longest Eon in geological history and witnessed the assemblies and breakups of the Columbia and Rodinia supercontinents. The Tarim Craton has been proposed to be a building block of these supercontinents. However, its tectonic evolution during late Paleoproterozoic to earliest Neoproterozoic (ca. 1.8–0.8 Ga) has been poorly understood, due to the paucity of geological record. In this paper, we present U-Pb and Lu-Hf isotopic data for detrital zircons from the metasediments of the early Neoproterozoic Paergangtag Group and the Paleoproterozoic Xinditag Group in the Kuruktag area, northern Tarim Craton. Although formed approximately 1 billion years later, the Paergangtag Group contains detrital zircons almost identical to those in the Xinditag Group. LA-ICP-MS U-Pb dating yields a ca. 2.0 Ga age peak, as well as a group of older zircons of ca. 2.5 Ga in six samples from these two groups. Lu-Hf data show that the ca. 2.0 Ga zircons have variable eHf(t) values (−28.1 to 0.1), indicating the detritus were mostly derived from reworked continental crusts. The older zircons around 2.5 Ga have both negative and positive eHf(t) values (−28.5 to 9.5), indicating a prolonged and complicated crustal growth and reworking process in the source area. It is inferred that the zircons in these samples were likely derived from southeastern Tarim Craton, where a ca. 2.0 Ga orogenic event has been documented. The fact that the Neoproterozoic Paergangtag Group contains only Paleoproterozoic and older zircons suggests that the Tarim Craton was not involved in the Grenville Orogeny, which developed between the colliding continents in the interior of the Rodinia Supercontinent. In contrast, the Tarim Craton was probably on the periphery of the Rodinia Supercontinent and was involved in the peripheral subduction zone of the supercontinent shortly after the deposition of the Paergangtag Group. Our new data imply that the Tarim Craton might have been a tectonically stable continent for nearly 1 billion years from ca. 1.8 to 0.9 Ga.

DNA damage repair plays essential roles in drug resistance, especially resistance to Poly (ADP-ribose) polymerase (PARP) inhibitors in the clinic. A subset of DNA repair proteins such as Breast cancer gene 1 (BRCA1), BRCA2 and RecA homolog (RAD51) are client proteins of heat shock protein 90 (Hsp90). Clearance of these DNA repair proteins by inhibition of Hsp90 is a promising strategy for overcoming resistance to PARP inhibitors. Here we report the pharmacological analysis of the highly potent second-generation Hsp90 inhibitor, ganetespib. Methods Nuclear BRCA1, BRCA2, and RAD51 expression in breast cancer cells were detected by subcellular fractionation and western blot analysis. Formation of nuclear RAD51 and γ-H2AX foci was analyzed by immunofluorescent staining. The cytotoxicity of ganetespib and ABT-888 in breast cancer cells were evaluated by cell proliferation, colony survival, and apoptosis assay. To investigate the efficacy of this therapy in vivo, SCID mice bearing MCF7 xenografts were treated with ganetespib and ABT-888, both as single agents and in combination. Results Ganetespib significantly destabilized nuclear BRCA1, BRCA2, and RAD51, and efficiently disrupted homologous recombination-mediated DNA double-strand break repair in breast cancer cells. The synergistic antitumor effects of ganetespib and the PARP inhibitor, ABT-888 were observed, and concurrent treatment with both inhibitors synergistically inhibited xenograft tumor growth. Importantly, the combined treatment was well tolerated, without significant loss of body weight or major histological changes in the breast cancer xenograft model. Conclusion These data provide a novel strategy for the treatment of breast cancer with wild type BRCA1 using combination therapy targeting Hsp90 to overcome resistance to PARP inhibitors.

miR-122, a liver-specific tumor suppressor microRNA, is frequently down-regulated in hepatocellular carcinoma (HCC). LNP-DP1, a cationic lipid nanoparticle formulation, was developed as a vehicle to restore deregulated gene expression in HCC cells by miR-122 delivery. LNP-DP1 consists of 2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), egg phosphatidylcholine, cholesterol and cholesterol-polyethylene glycol. In vitro , LNP-DP1-mediated transfection of a miR-122 mimic to HCC cells down-regulated miR-122 target genes by >95%. In vivo , siRNAs/miRNAs encapsulated in LNP-DP1 were preferentially taken up by hepatocytes and tumor cells in a mouse HCC model. The miR-122 mimic in LNP-DP1 was functional in HCC cells without causing systemic toxicity. To demonstrate its therapeutic potential, LNP-DP1 encapsulating miR-122 mimic was intratumorally injected and resulted in ~50% growth suppression of HCC xenografts within 30days, which correlated well with suppression of target genes and impairment of angiogenesis. These data demonstrate the potential of LNP-DP1-mediated microRNA delivery as a novel strategy for HCC therapy. From the Clinical Editor In this study, LNP-DP1 –a cationic lipid nanoparticle formulation –is reported as a vehicle to restore deregulated gene expression in hepatic carcinoma cells by siRNA and miRNA delivery using a mouse model. Further expansions to this study may enable transition to clinical trials of this system.

Endocrine resistance is a major challenge in the management of estrogen receptor (ER)-positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that noncanonical Hedgehog (Hh) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role in regulating Hh signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hh-signaling molecules SMO and GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hh marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G1–S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen-resistant xenografts with anti-Hh compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 patients with breast cancer. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hh signaling that promotes tamoxifen resistance. Targeting Hh pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine-resistant breast cancer. Cancer Res; 72(19); 5048–59. ©2012 AACR.

Purpose: Aberrant hedgehog (Hh) signaling has been reported in various cancers including breast cancers and clinical trials targeting this pathway are currently ongoing. Preclinical evidence suggests that increased ligand-dependent Hh signaling in breast tumor epithelial (E) cells cross-talks and activates Hh pathway in the stroma (S) but the clinical implication of this E/S interaction is unknown. We sought to determine the expression of Hh proteins in the E and S compartments of primary breast tumor samples and correlate with clinical outcomes. Methods: Using tissue microarray (TMA) of ∼500 primary breast cancer samples (OSU 2009C009 A) that includes both primary breast tumor and axillary metastasis, the expression pattern of the key Hh signaling proteins (Shh, Gli-1, SMO, Ptch1) and a target gene of the pathway (BMI1) was determined by immunohistochemistry (IHC) in both the epithelial and stromal tissues and compared to other known prognostic/predictive markers such as age, stage, estrogen/progesterone receptor (ER/PR)/HER2 status and to disease-free survival (DFS). IHC was performed using Benchmark LT automated system from Ventana Medical Systems using previously published methods (Nuovo GJ, Nature protocols, 2009). Scoring was done by combining the intensity and percentage of cells staining with respective antibodies by three independent measurements. Results: Analysis of a total of 315 primary breast tumors revealed the following percentage of tumors with high expression of Hh proteins in the E/S compartments respectively: Shh (72/31%), Gli-1 (69/53%), SMO (40/64%), and Ptch-1 (93/74%). Analyzing the interaction between the epithelial and stromal expressions of these proteins, we found positive correlation between i) high Shh and SMO in the epithelial cells and Gli-1 in the stroma, and ii) high Gli-1 in the epithelial cells and target protein Bmi1 in the stroma. High intensity staining of Gli-1 in the tumor epithelial cells was significantly associated with higher stage, grade, ER negative status and worse DFS. Adjusting for stage and ER status, tumors with increased epithelial Gli-1 expression was still significantly associated with worse DFS (p=0.0131, survival analysis) when compared to tumors with low expression. In particular, among the ER negative and node positive patients higher Gli-1 expression in epithelial cells was very significantly associated with poor DFS (p= Conclusions: We report here for the first time a positive correlation between expression of Hh proteins in the stromal and epithelial compartment of primary breast tumors. Furthermore, we observed that higher Gli-1 expression in the tumor epithelial cells was associated with worse DFS, particularly in the ER negative, node-positive tumors suggesting that aberrant Hh signaling may contribute to drug-resistance and hence a rationale therapeutic target. Further correlative studies between clinical parameters and additional Hh target genes in these tumors are in progress. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-9.

We have shown earlier that miR-221 and -222 are up-regulated in tamoxifen-resistant MCF-7 (OHT(R)) cells and Her2-positive human breast tumors when compared with Her2 negative tumors. In this study, we report markedly enhanced expression of miR-181b in OHT(R) cells and endocrine-resistant tumors. Further, anti-miR-222 or -181b in combination with tamoxifen suppressed growth of tamoxifen-resistant xenografts in mice. Luciferase reporter assay and expression analysis showed that TIMP3, a tissue metalloproteinase inhibitor, is a common target of miR-221/222 and -181b. In situ hybridization and immunohistochemical analysis demonstrated reciprocal relationships between TIMP3 and miR-221/222/181b expression in primary human breast carcinomas. Ectopic expression of TIMP3 inhibited growth of the OHT(R) cells, and its depletion in MCF-7 cells reduced sensitivity to tamoxifen in vitro and in vivo. EGF-induced MAPK and AKT phosphorylation were significantly higher in OHT(R) cells and miR-221/222-overexpressing MCF-7 cells than in control cells, which suggests modulation of mitogenic signaling by TIMP3 and the miRs. On the contrary, phosphoMAPK and phosphoAKT levels were diminished in TIMP3-overexpressing OHT(R) cells and increased in TIMP3-depleted MCF-7 cells. Low levels of estrogen or tamoxifen elicited similar differences in phosphoMAPK levels in these cells. Reduced levels of TIMP3 facilitated growth of tamoxifen-resistant cells by alleviating its inhibitory effect on ADAM10 and ADAM17, which are critical for OHT(R) cell growth. In conclusion, miR-221/222 and -181b facilitate growth factor signaling in tamoxifen-resistant breast cancer by down-regulating TIMP3, and corresponding anti-miRs can be used to render these tumors responsive to tamoxifen.

Hepatocellular carcinoma (HCC) is the third most common cause of mortality due to malignancy next to gastric cancer and esophageal cancer. Several causal factors have been proposed to be involved in the pathogenesis of HCC including regional and age difference, hepatitis virus, aflatoxin, chemicals, liver cirrhosis, and family heredity. Compared to the initial symptoms of HCC, the late symptoms are more obvious, which are liver pain, fatigue, emaciation, jaundice, and ascites. This paper summarized 30 biomarkers from organs, tissues, cells, and subcellular systems to be used for the diagnosis, detection, staging, and evaluation of the HCC so as to predict or prognoses diseases. The biomarker degrees of healthy people have a certain range of indicators. Pathological and clinical diagnostic methods are mainly used to detect various biomarkers related to HCC, such as the common detection of alpha-fetoprotein to detect HCC. Diverse indicators are determined by the modern technology so that we can explore and clarify the possible indicators associated with the pathogenesis of diseases in the organisms. In general, if one or more biomarkers are beyond the normal range, it would predict the presence of HCC in the body. Here, we try to provide a significant contribution toward clinical screening, prediction, diagnosis, treatment, and follow-up monitoring of HCC and related diseases through elucidating the conception, production and influencing factors, sources, and biochemical indicator-associated tumor markers.

The potential of chaotifying vibration isolation systems to reduce line spectra of underwater vehicle and improve its capability of concealment have recently reported. Notice that for an isolation system, the amplitude of chaotifying vibration is, in general, larger than that of its specified periodic motion subject to the inherent characteristic of chaotic behavior. Therefore, there exists a conflict between the line spectra reduction based on chaotifying vibration responses and the capability of vibration isolation. In this paper, a method based on the modified projective synchronization (MPS) is developed to improve vibration isolation while the chaotifying vibration signals with broad band frequency are utilized to achieve line spectra reduction. The key to this solution is the scaling factors of MPS which enable us to proportionally diminish the vibration amplitudes of the isolated equipment. The feasibility of the methodology in practical engineering is illustrated with the application to acoustic stealth of submarines.