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CRISPR-Cas modules serve as the adaptive nucleic-acid immune systems for prokaryotes, and provide versatile tools for nucleic-acid manipulation in various organisms. Here, we discovered a new miniature type V system, CRISPR-Casπ (Cas12l) (∼860 aa), from the environmental metagenome. Complexed with a large guide-RNA (∼170 nt) comprising the tracrRNA and crRNA, Casπ (Cas12l) recognizes a unique 5’ C-rich PAM for DNA cleavage under a broad range of biochemical conditions, and generates gene editing in mammalian cells. Cryo-EM study reveals a ‘bracelet’ architecture of Casπ effector encircling the DNA target at 3.4-Å resolution, substantially different from the canonical ‘two-lobe’ architectures of Cas12 and Cas9 nucleases. And the large guide-RNA serves as a ‘two-arm’ scaffold for effector assembly. Our study expands the knowledge of DNA targeting mechanisms by CRISPR effectors, and offers an efficient but compact platform for DNA manipulations.

ObjectiveThe systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing.DesignWhole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells.ResultsBased on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells.ConclusionOur results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

Gastric cancer (GC) is currently the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs), transcriptional products with more than 200 nucleotides, are not as well-characterized as protein-coding RNAs. Accumulating evidence has recently revealed that maladjustments of diverse lncRNAs may play key roles in multiple genetic and epigenetic phenomena in GC, affecting all aspects of cellular homeostasis, such as proliferation, migration, and stemness. However, the full extent of their functionality remains to be clarified. Considering the lack of viable biomarkers and therapeutic targets, future research should be focused on unravelling the intricate relationships between lncRNAs and GC that can be translated from bench to clinic. Here, we summarized the state-of-the-art advances in lncRNAs and their biological functions in GC, and we further discuss their potential diagnostic and therapeutic roles. We aim to shed light on the interrelationships between lncRNAs and GC with respect to their potential therapeutic applications. With better understanding of these relationships, the biological functions of lncRNAs in GC development will be exploitable, and promising new strategies developed for the prevention and treatment of GC.

Long non-coding RNAs (lncRNAs), a type of transcriptional products with more than 200 nucleotides in length, have been less characterized compared to protein-coding RNAs so far. However, it is increasingly evident that lncRNAs are key players involved in multiple genetic and epigenetic activities during the carcinogenesis of neoplastic diseases. Currently, accumulating data have pointed out the close connection between lncRNAs and esophageal carcinoma (EC), shedding light on further unravelling the complexity of lncRNAs and EC. Methods In this review, we thoroughly collect the evidence regarding original studies on EC-related lncRNAs by searching in MEDLINE/PubMed, Embase and WOS/SCI. We especially focus on summarizing EC-related lncRNAs based upon more updated evidence, and further discuss their different features from various perspectives, including regulatory mechanisms, functional roles in cancer hallmarks, as well as potential diagnostic and therapeutic applications, which would together reveal the complexity of lncRNAs and EC for potential clinical applications. Results We discuss over thirty EC-related lncRNAs in total, most of which function as oncogenes that promote cancer development, while the others function as tumor suppressors. Regulatory mechanisms included sponging miRNAs, direct interaction with proteins, and exosome visicle-based intercellular communication. Based upon these modes of actions, lncRNAs play multiple roles in cancer hallmarks such as uncontrolled cell growth, evasion of programmed cell death, invasion and metastasis. Moreover, lncRNAs packaged in exosomes have unique potency to serve as diagnostic biomarkers; some lncRNAs show great potential to predict patients' chemical resistance and may be crucial targets to improve chemoradiotherapy and targeted therapy. Conclusion Over the past few years, the research of EC-related lncRNAs maintain obviously rapid development, yet further exploration of exact mechanisms and clinical applications that lncRNAs can offer need to be done. Indeed, LncRNAs hold the promise of being applied in multiple clinical scenarios, especially early diagnosis of EC, improvement of sensitivity to chemotherapy/radiotherapy, and development of small-molecule targeted drugs.

Clinical staining and targeting CREB3L1 facilitates precise stratification and a potential treatment strategy for thyroid cancer., Understanding of dedifferentiation, an indicator of poo prognosis for patients with thyroid cancer, has been hampered by imprecise and incomplete characterization of its heterogeneity and its attributes. Using single-cell RNA sequencing, we explored the landscape of thyroid cancer at single-cell resolution with 46,205 cells and delineated its dedifferentiation process and suppressive immune microenvironment. The developmental trajectory indicated that anaplastic thyroid cancer (ATC) cells were derived from a small subset of papillary thyroid cancer (PTC) cells. Moreover, a potential functional role of CREB3L1 on ATC development was revealed by integrated analyses of copy number alteration and transcriptional regulatory network. Multiple genes in differentiation-related pathways (e.g., EMT) were involved as the downstream targets of CREB3L1, increased expression of which can thus predict higher relapse risk of PTC. Collectively, our study provided insights into the heterogeneity and molecular evolution of thyroid cancer and highlighted the potential driver role of CREB3L1 in its dedifferentiation process.

Programmed cell death (PCD)—apoptosis, autophagy and programmed necrosis—is any pathological form of cell death mediated by intracellular processes. Ototoxic drugs, ageing and noise exposure are some common pathogenic factors of sensorineural hearing loss (SNHL) that can induce the programmed death of auditory hair cells through different pathways, and eventually lead to the loss of hair cells. Furthermore, several mutations in apoptotic genes including DFNA5, DFNA51 and DFNB74 have been suggested to be responsible for the new functional classes of monogenic hearing loss (HL). Therefore, in this review, we elucidate the role of these three forms of PCD in different types of HL and discuss their guiding significance for HL treatment. We believe that further studies of PCD pathways are necessary to understand the pathogenesis of HL and guide scientists and clinicians to identify new drug targets for HL treatment., The authors review accumulating evidence pointing out that programmed cell death pathways, including apoptosis, autophagy and necrosis, play key roles in ultimate fates of auditory hair cells, when cells suffer adverse factors. These three forms of PCD may jointly decide occurrence of hearing loss.

Objective: The objective of this study was to summarize the clinicopathological characteristics of the CLDN18-ARHGAP fusion gene in gastric cancer patients.Background: The CLDN18-ARHGAP26 fusion gene is one of the most frequent somatic genomic rearrangements in gastric cancer, especially in the genomically stable (GS) subtype. However, the clinical and prognostic meaning of the CLDN18-ARHGAP fusion in gastric cancer patients is unclear.Methods: Studies that investigated CLDN18-ARHGAP fusion gastric cancer patients were identified systematically from the PubMed, Cochrane, and Embase databases through the 28th of February 2020. A systematic review and meta-analysis were performed to estimate the clinical significance of CLDN18-ARHGAP fusion in patients.Results: A total of five eligible studies covering 1908 patients were selected for inclusion in the meta-analysis based on specified inclusion and exclusion criteria. Several fusion patterns were observed linking CLDN18 and ARHGAP26 or ARHGAP6, with the most common type being CLDN18/exon5-ARHGAP26/exon12. The survival outcome meta-analysis of the CLDN18-ARHGAP fusion gene showed that it was associated with overall survival outcomes in gastric cancer (HR, 2.03, 95% CI 1.26–3.26, P < 0.01, random-effects). In addition, diffuse gastric cancer had a greater proportion of CLDN18-ARHGAP fusions than intestinal gastric cancer (13.3%, 151/1,138 vs. 1.8%, 8/442; p < 0.001). Moreover, gastric cancer patients with the CLDN18-ARHGAP fusion gene are more likely to be female or have a younger age, lymph node metastasis and advanced TNM stages.Conclusion: The CLDN18-ARHGAP fusion is one of the molecular characteristics of diffuse gastric cancer and is also an independent prognostic risk factor for gastric cancer. In addition, it is also related to multiple clinical characteristics, including age, sex, lymph node metastasis and tumor stage. However, the mechanism of the CLDN18-ARHGAP fusion gene and potential targeted therapeutic strategies need further exploration.

Objective Interleukin-21 (IL-21) contributes to expansion, differentiation, and modulation of various immunocompetent cells. Deregulated production of IL-21 plays a role of cardinal significance in the pathogenesis of systemic lupus erythematosus (SLE). We aimed to determine whether single nucleotide polymorphisms (SNP) near the IL-21 gene have significant association with SLE susceptibility and the T helper-related inflammatory cytokine profile of SLE patients. Methods We enrolled 460 SLE patients and 460 healthy controls. Whole genome analysis was used to investigate different genes including IL-21. Loci rs11725913, rs11937669, rs7676539, rs111438679, rs115935829, rs373549, rs4487356, and rs79923870 were further genotyped using an improved multiplex ligation detection reaction technique. Susceptibility, levels of Th-related inflammatory cytokines, and some clinical indexes of SLE patients were analyzed. Results rs11725913 and rs11937669 were identified for association with SLE in Chinese Han Population. The allelic frequency of rs11725913 approached significance (odds ratio (OR) (95% Confidence Interval (CI)) = 1.431 (1.122–1.825), P = 0.004). GT genotype at rs11725913 and GA genotype at rs11937669 were associated with SLE susceptibility (OR (95% CI) = 1.448 (1.074–1.952), P = 0.015; OR (95%CI) = 1.356 (1.013–1.815), P = 0.040, respectively). Dominant model analysis provided us with further validation (rs11725913: OR (95%CI) = 1.502 (1.126–2.004), P = 0.006; rs11937669: OR (95%CI) = 1.356 (1.025–1.793), P = 0.033). Cases with rs11937669 risk GA-genotype had higher serum IL-6 concentration than others ( P = 0.022). Dominant model analysis showed that patients with the wild type (AA-genotype) at rs11937669 had significantly lower soluble CD40 ligand ( P = 0.029) but higher IL-17A ( P = 0.040) compared with others. Cases carrying rs11725913 T allele had higher gamma glutamyl transpeptidase level ( P = 0.045) than those without. Conclusions We identified two new loci, rs11725913 and rs11937669, associated with SLE risk in Chinese Han population. This research provided a new insight into the significant relationship between polymorphisms upstream IL-21 and Th17 inflammatory response, which suggest that the sequence upstream of the IL-21 gene is an important region involved in the Th17-related pathway.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the ERG gene (rs2836365; P = 3.76 × 10−8; odds ratio [OR] = 1.56), with independent validation (P = .01; OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the ERG risk variant rose with increasing Native American genetic ancestry. The ERG risk genotype was underrepresented in ALL with the ETV6-RUNX1 fusion (P < .0005) but enriched in the TCF3-PBX1 subtype (P < .05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.

As a widely used anticancer and immunosuppressive agent, methotrexate (MTX) can induce multiple adverse drug reactions (ADRs), such as gastrointestinal toxicity, the mechanisms are poorly understood. Gut microbiota has been widely reported to be associated with the onset of multiple diseases as well as treatment outcomes of different drugs. In this study, mucosal injury was observed in MTX-treated mice, leading to significant changes in macrophages (i.e., M1/M2 ratio, P

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UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, we discovered a small molecule 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86, and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, we found that 33i induced autophagy via the ULK complex in SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.

Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 9f induced ACD pathways involved in HMGB1, VDAC1/2, and eEF2. Moreover, 9f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.

Protein kinases are well-known to orchestrate the activation of signaling cascades in response to extracellular and intracellular stimuli to control cell proliferation and survival. The perturbation of such kinases by some mutation or abnormal protein expressions has been closely linked to cancer. Drug development aimed at several targetable kinases may alter their participated pathways that are able to trigger carcinogenesis. A series of small-molecule drugs have been approved for the current cancer therapy. However, their complicated inherent mechanisms may lead to the resistance to such small molecules. Consequently, development of new dual-target kinase drugs simultaneously aimed at two targetable kinases may improve their anti-tumor efficiency and solve resistant mechanism problems. In this review, we focus on summarizing an overview of the current strategies of dual-target kinase drug design, including medicinal chemistry strategies and computational approaches. Taken together, we believe the above-mentioned strategies will provide a new insight into future directions of dual-target kinase drug design to improve potential cancer therapeutics.

Dermatofibrosarcoma protuberans (DFSP) is soft tissue malignancy which is locally aggressive, slow-growth, rarely metastasizing but recurs frequently after surgical excision. Fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP) is a variant of DFSP with a higher risk of recurrence and metastasis. For treatment of metastatic DFSP, antiangiogenesis therapy is an important therapeutic option, which is beneficial in increasing the efficacy of chemotherapy. Apatinib is a novel vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor and revealed potential anti-tumor efficacy in some types of sarcomas. However, there is still no report of apatinib as an angiogenesis therapy for metastatic DFSP to date. Herein we first describe a case of FS-DFSP relapsed and metastasized post multiple surgeries and adjuvant radiotherapy responded to apatinib in combination with chemotherapy, indicating apatinib may be a potential therapeutic option for metastatic DFSP.

// Qianqian Hou 1, * , Fei Liao 1, * , Shouyue Zhang 1, * , Duyu Zhang 1, * , Yan Zhang 2 , Xueyan Zhou 1 , Xuyang Xia 1 , Yuanxin Ye 8 , Hanshuo Yang 3 , Zhaozhi Li 1 , Leiming Wang 4 , Xi Wang 5 , Zhigui Ma 6 , Yiping Zhu 6 , Liang Ouyang 3 , Yuelan Wang 1 , Hui Zhang 7 , Li Yang 3 , Heng Xu 1, 8 , Yang Shu 1 1 Department of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China 2 Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China 3 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China 4 Department of Molecular Biology, Baylor College of Medicine, Houston, Texas, USA 5 Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angles, Los Angles, California, USA 6 Department of Pediatric Hematology/Oncology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China 7 Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA 8 Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China * These authors contributed equally to this work Correspondence to: Heng Xu, email: xuheng81916@scu.edu.cn Yang Shu, email: shuyang1986@gmail.com Keywords: GATA3, acute lymphoblastic leukemia, tissue-specific regulation network, microarray datasets Received: February 21, 2017 Accepted: March 11, 2017 Published: March 21, 2017 ABSTRACT GATA3 polymorphisms were reported to be significantly associated with susceptibility of pediatric B-lineage acute lymphoblastic leukemia (ALL), by impacting on GATA3 expression. We noticed that ALL-related GATA3 polymorphism located around in the tissue-specific enhancer, and significantly associated with GATA3 expression. Although the regulatory network of GATA3 has been well reported in T cells, the functional status of GATA3 is poorly understood in B-ALL. We thus conducted genome-wide gene expression association analyses to reveal expression associated genes and pathways in nine independent B-ALL patient cohorts. In B-ALL patients, 173 candidates were identified to be significantly associated with GATA3 expression, including some reported GATA3 -related genes (e.g., ITM2A ) and well-known tumor-related genes (e.g., STAT4 ). Some of the candidates exhibit tissue-specific and subtype-specific association with GATA3 . Through overexpression and down-regulation of GATA3 in leukemia cell lines, several reported and novel GATA3 regulated genes were validated. Moreover, association of GATA3 expression and its targets can be impacted by SNPs (e.g., rs4894953), which locate in the potential GATA3 binding motif. Our findings suggest that GATA3 may be involved in multiple tumor-related pathways (e.g., STAT/JAK pathway) in B-ALL to impact leukemogenesis through epigenetic regulation.

UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates. After rounds of kinase and anti-proliferative activity screening, we discovered the small molecule, LYN-1604, to be the best candidate for a ULK1 agonist. Additionally, we identified that three amino acid residues (LYS50, LEU53, and TYR89) were key to the activation site of LYN-1604 and ULK1 by site-directed mutagenesis and biochemical assays. Subsequently, we demonstrated that LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. To further explore LYN-1604-induced autophagic mechanisms, we found some potential ULK1 interactors, such as ATF3, RAD21, and caspase3, by performing comparative microarray analysis. Intriguingly, we found that LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. Moreover, we demonstrated that LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy.

Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13-10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.

International audience; Cet article montre l’intérêt de la mémoire du passé enregistrée dans les paysages superficiels et souterrains des milieux karstiques. Les karsts de la Chine du sud-ouest renferment une grande variété de milieux étagés de 200 à 5 000 m d’altitude. Parmi ces milieux, ceux de la moyenne montagne (entre 500 et 1 500 m d’altitude) se distinguent car ce sont eux qui ont été les plus fortement perturbés par l’homme : pour cette raison, nos exemples s’intéresseront plus particulièrement aux provinces du Guizhou et du Hubei. Remonter la flèche du temps permet de comprendre l’évolution des paysages (§ I) avec l’homme, (§ II) sans l’homme et (§ III) de reconstituer les paléo-paysages. I- Le temps des hommes s’inscrit dans le temps court depuis la période contemporaine jusqu’au temps des premières sociétés (0-11 000 ans). Deux exemples ont été retenus : 1) pour l’exokarst, l’étude des dents de pierre comme indicateur d’une érosion des sols d’origine anthropique (Guizhou) ; 2) pour l’endokarst, une coupe sédimentaire dans le réseau de Dadong permet d’estimer un début d’agriculture sur brûlis légèrement antérieur à 10 000 ans BP (Hubei). II- Le temps de la géomorphologie est celui des paysages fonctionnels. Il correspond au temps moyen à mi-long (11 000 ans à 1-5 Ma). Les principaux moteurs qui régissent l’évolution des milieux sont 1/ le climat : une stalagmite active du Hubei à faible croissance a enregistré, au stade isotopique 3, une phase de type biostasique et 2/ la tectonique : les grottes-tunnels étagées du Guizhou représentent les jalons de la phase himalayenne. La transition du temps moyen au temps long (1-5 Ma) doit être recherchée au niveau de la haute surface et ses jalons karstiques (ponts naturels, mégadolines d’effondrement, couloirs résiduels et paléo-pertes perchées). L’abaissement des surfaces a fait disparaître les couches les plus récentes, notamment les basaltes du Permien. De ces roches, aujourd’hui disparues, il reste les altérites. III- Le temps de la géologie est celui du temps long (>5 Ma). La succession des cycles orogéniques a provoqué la disparition d’une colonne sédimentaire de plusieurs kilomètres, soit la disparition complète de paysages karstiques enregistrés désormais dans les sédiments marins, lacustres et continentaux. La fonction conservatrice des archives karstiques joue encore un certain rôle avec le maintien de deux types d’archives : les bassins rouges et les paléokarsts. Aujourd’hui, l’un des problèmes majeurs de ces régions réside dans l’érosion accélérée des altérites, consécutive des déboisements. Cette érosion constitue une perte irrémédiable à l’échelle de l’homme (temps court) car les calcaires sous-jacents (temps long) sont trop pauvres en insolubles pour permettre la reconstitution des sols (temps moyen).

Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the

Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC., Signet-ring cell carcinoma (SRCC) is a unique type of gastric cancer with no prognostic features. Here, the authors report a CLDN18-ARHGAP26/6 gene fusion in patients with a high signet-ring cell content, poor survival outcomes, and who experience no benefit from platinum/fluoropyrimidines-based chemotherapy.

Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.

Non‐small‐cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never‐smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never‐smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never‐smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well‐known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer‐associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer‐related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer‐related structural variations (e.g., EML4‐ALK and KIF5B‐RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK (SMG6‐ALK) and RET (JMJD1C‐RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never‐smoker patients with LUAD when compared with the in‐house noncancer database (p, What's new? Young patients with non‐small‐cell lung cancer (NSCLC) represent a distinct disease entity: they are often female, never smoked and usually present with lung adenoma carcinomas. Here the authors performed whole‐genome sequencing in patients with early‐onset NSCLC who never smoked and find an overall lower mutation burden and fewer classic driver substitutions. However, oncogenic fusions were found more frequently, underscoring that a unique molecular make‐up defines this specific subgroup of cancer patients.

The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

Arctigenin (ARG) has been previously reported to exert diverse biological activities including anti-proliferation, anti-inflammatory, and antiviral, etc. In the current study, the anti-metastasis and anti-angiogenesis activities of ARG were investigated. To further understand how ARG played these bioactivities, proteomic approaches were used to profile the proteome changes in response to ARG treatment using 2DE-MS/MS. Using these approaches, a total of 50 differentially expressed proteins were identified and clustered. Bioinformatics analysis suggested that multiple signalling pathways were involved. Moreover, ARG induced anti-metastatic and anti-angiogenesis activities were mainly accompanied by a deactivation of the Wnt/β-catenin pathway in HCT116 cells.

Autophagy, the cell process of self-digestion, plays a pivotal role in maintaining energy homoeostasis and protein synthesis. When required, it causes degradation of long-lived proteins and damaged organelles, indicating that it may play a dual role in cancer, by both protecting against and promoting cell death. The autophagy-related gene (Atg) family, with more than 35 members, regulates multiple stages of the process. Serine/threonine protein kinase Atg1 in yeast, for example, can interact with other ATG gene products, functioning in autophagosome formation. One mammalian homologue of Atg1, UNC-51-like kinase 1 (ULK1) and its related complex ULK1-mAtg13-FIP200 can mediate autophagy under nutrient-deprived conditions, by protein-protein interactions and post-translational modifications. Although specific mechanisms of how ULK1 and its complex transduces upstream signals to the downstream central autophagy pathways is not fully understood, past studies have indicated that ULK1 can both suppress and promote tumour growth under different conditions. Here, we summarize some properties of ULK1 which can regulate autophagy in cancer, which may shed new light on future cancer therapy strategies, utilizing ULK1 as a potential new target.

Polygonatum odoratum lectin (POL), a mannose-binding GNA-related lectin, has been reported to display remarkable anti-proliferative and apoptosis-inducing activities toward a variety of cancer cells; however, the precise molecular mechanisms by which POL induces cancer cell death are still elusive. In the current study, we found that POL could induce both apoptosis and autophagy in human MCF-7 breast cancer cells. Subsequently, we found that POL induced MCF-7 cell apoptosis via the mitochondrial pathway. Additionally, we also found that POL induces MCF-7 cell apoptosis via EGFR-mediated Ras-Raf-MEK-ERK pathway, suggesting that POL may be a potential EGFR inhibitor. Finally, we used proteomics analyses for exploring more possible POL-induced pathways with EGFR, Ras, Raf, MEK and ERK, some of which were consistent with our in silico network prediction. Taken together, these results demonstrate that POL induces MCF-7 cell apoptosis and autophagy via targeting EGFR-mediated Ras-Raf-MEK-ERK signaling pathway, which would provide a new clue for exploiting POL as a potential anti-neoplastic drug for future cancer therapy.

Family with sequence similarity 20, member C (Fam20C) is a physiological Golgi casein kinase that phosphorylates multiple secreted proteins. Recently, it has been reported that Fam20C can be identified as a novel kinase target for therapeutic development. Thus, inhibition of Fam20C will be a potential therapeutic strategy to prevent tumor cell progression and metastasis. In our study, based upon the systems-biology network, molecular modeling and molecular dynamics (MD) simulations, we discovered a novel Fam20C inhibitor (FL-1607) with potent anti-proliferative effects on triple-negative breast cancer (TNBC) cells. Subsequently, we found that this Fam20C inhibitor could induce apoptosis and inhibit cell migration in MDA-MB-468 cells. Together, these findings would provide a new clue to the exploration of more novel Fam20C inhibitors for future TNBC therapy.

The aim of this study was to explore the autophagy-related protein 4B(ATG4B) and its targeted candidate agonist in triple-negative breast cancer (TNBC) therapy. In this study, the identification of Atg4B as a novel breast cancer target for screening candidate small molecular agonists was performed by phylogenetic analysis, network construction, molecular modelling, molecular docking and molecular dynamics (MD) simulation. In vitro, MTT assay, electron microscopy, western blot and ROS measurement were used for validating the efficacy of the candidate compounds. We used the phylogenetic analysis of Atg4B and constructed their protein-protein interaction (PPI) network. Also, we screened target compounds of Atg4 proteins from Drugbank and ZINC. Flubendazole was validated for its anti-proliferative efficacy in MDA-MB-231 cells. Further MD simulation results supported the stable interaction between Flubendazole and Atg4B. Moreover, Flubendazole induced autophagy and increased ROS production. In conclusion, in silico analysis and experimental validation together demonstrate that Flubendazole can target Atg4B in MDA-MB-231 cells and induce autophagy, which may shed light on the exploration of this compound as a potential new Atg4B targeted drug for future TNBC therapy.

Natural products are chemical compounds or substances produced naturally by living organisms. With the development of modern technology, more and more plant extracts have been found to be useful to medical practice. Both micromolecules and macromolecules have been reported to have the ability to inhibit tumour progression, a novel weapon to fight cancer by targeting its 10 characteristic hallmarks. In this review, we focus on summarizing plant natural compounds and their derivatives with anti-tumour properties, into categories, according to their potential therapeutic strategies against different types of human cancer. Taken together, we present a well-grounded review of these properties, hoping to shed new light on discovery of novel anti-tumour therapeutic drugs from known plant natural sources.

Eukaryotic elongation factor-2 kinase (eEF2K), encoded by the EEF2K gene, is well-known to be a Ca(2+)/calmodulin (CaM)-dependent kinase which can negatively modulate protein synthesis. It is highly conserved among eukaryotes from mammals to invertebrates, of which human and mouse may have 99 % overall amino acid identity. This kinase can phosphorylate eukaryotic elongation factor-2 (eEF2) or undergo the process of autophosphorylation at multiple sites to inhibit its function in translation elongation. Due to the fact that regulation of eEF2 by eEF2K is an evolutionarily conserved mechanism, eEF2K activity may confer tumor cell adaption to metabolic stress under acute nutrient depletion, and the high expressed level of eEF2K has been found in several types of malignancies. eEF2K may modulate the expression of some apoptotic proteins such as XIAP, c-FLIPL, Bcl-XL, PI3KCI and p70(S6K) to inhibit apoptotic process in cancer. On the other hand, it plays a regulatory role in autophagy involved in mTORC1, AMPK and Atg8, thereby promoting cancer cell survival. Additionally, eEF2K may play a crucial role in the crosstalk between apoptosis and autophagy in cancer. Collectively, these findings have led to the conclusions that eEF2K may contribute to carcinogenesis, and thus being utilized as a potential target for future cancer therapy.

MicroRNAs are a class of small, non-coding RNAs that can negatively regulate protein-coding genes, and are associated with almost all known physiological and pathological processes, especially cancer. The number of studies documenting miRNA expression patterns in malignancy continues to expand rapidly, with continuously gained critical information regarding how aberrantly expressed miRNAs may contribute to carcinogenesis. miRNAs can influence cancer pathogenesis, playing a potential role as either oncogenes or tumour suppressors. Recently, several miRNAs have been reported to exert different regulatory functions in oesophageal cancer - the carcinoma typically arising from the epithelial lining of the oesophagus. These miRNAs also have potential clinical applications towards developing biomarkers or targets for possible use in diagnosis or therapy in oesophageal cancer. In this review, we have summarized the two (oncogenic or tumour suppressive) roles of miRNAs here, and their applications as potential biomarkers or therapeutic targets, which may illuminate future treatment for oesophageal cancer.