An Overview of Advances in Rare Cancer Diagnosis and Treatment.

Cancer stands as the leading global cause of mortality, with rare cancer comprising 230 distinct subtypes characterized by infrequent incidence. Despite the inherent challenges in addressing the diagnosis and treatment of rare cancers due to their low occurrence rates, several biomedical breakthroughs have led to significant advancement in both areas. This review provides a comprehensive overview of state-of-the-art diagnostic techniques that encompass new-generation sequencing and multi-omics, coupled with the integration of artificial intelligence and machine learning, that have revolutionized rare cancer diagnosis. In addition, this review highlights the latest innovations in rare cancer therapeutic options, comprising immunotherapy, targeted therapy, transplantation, and drug combination therapy, that have undergone clinical trials and significantly contribute to the tumor remission and overall survival of rare cancer patients. In this review, we summarize recent breakthroughs and insights in the understanding of rare cancer pathophysiology, diagnosis, and therapeutic modalities, as well as the challenges faced in the development of rare cancer diagnosis data interpretation and drug development.

Targeting the DNA repair pathway for breast cancer therapy: Beyond the molecular subtypes.

DNA repair is a vital mechanism in cells that protects against DNA damage caused by internal and external factors. It involves a network of signaling pathways that monitor and transmit damage signals, activating various cellular activities to repair DNA damage and maintain genomic integrity. Dysfunctions in this repair pathway are strongly associated with the development and progression of cancer. However, they also present an opportunity for targeted therapy in breast cancer. Extensive research has focused on developing inhibitors that play a crucial role in the signaling pathway of DNA repair, particularly due to the remarkable success of PARP1 inhibitors (PARPis) in treating breast cancer patients with BRCA1/2 mutations. In this review, we summarize the current research progress and clinical implementation of BRCA and BRCAness in targeted treatments for the DNA repair pathway. Additionally, we present advancements in diverse inhibitors of DNA repair, both as individual and combined approaches, for treating breast cancer. We also discuss the clinical application of DNA repair-targeted therapy for breast cancer, including the rationale, indications, and summarized clinical data for patients with different breast cancer subtypes. We assess their influence on cancer progression, survival rates, and major adverse reactions. Last, we anticipate forthcoming advancements in targeted therapy for cancer treatment and emphasize prospective areas of development.

Establishment of a prognostic model toward lung squamous cell carcinoma based on m7G-related genes in the cancer genome atlas.

Lung squamous cell carcinoma (LUSC) is a non-small cell lung cancer with a poor prognosis owing to late diagnosis. New molecular markers are urgently needed to improve the diagnosis and prognosis of LUSC. 7-Methylguanosine (m7G) modifications, a tRNA modification, are common in eubacteria, eukaryotes, and a few archaea. These modifications promote the turnover and stability of some mRNAs to prevent mRNA decay, improve translation efficiency, and reduce ribosomal pausing but are associated with poor survival in human cancer cells. However, expression of m7G-related genes in LUSC and their association with prognosis remain unclear. In the present study, we identified nine differentially expressed genes related to prognosis by comparing the expression profiles of tumor tissues (502 LUSC reports) with normal tissues (49 adjacent nontumor lung tissue reports). The genes included six upregulated genes (KLK7, LCE3E, AREG, KLK6, ZBED2, and MAPK4) and three downregulated genes (ADH1C, NTS, and ERLIN2). Based on these nine genes, patients with LUSC were classified into low- and high-risk groups to analyze the trends in prognosis. We found that the nine m7G-related genes play important roles in immune regulation, hormone regulation, and drug sensitivity through pathways including antigen processing and presentation, adherent plaques, extracellular matrix receptor interactions, drug metabolism of cytochrome P-450, and metabolism of cytochrome P-450 to xenobiotics; the functions of these genes are likely accomplished in part by m6A modifications. The effect of m7G-related genes on the diagnosis and prognosis of LUSC was further indicated by population analysis.NEW & NOTEWORTHY Based on the differential expression of 7-methylguanosine (m7G) modification-associated genes between normal and lung squamous cell carcinoma (LUSC) tissues, and considering the performance of our m7G-related gene risk profiles as independent risk factors in predicting overall survival, we conclude that m7G modification is closely linked to the development of LUSC. In addition, this study offers a new genetic marker for predicting the prognosis of patients with LUSC and presents a crucial theoretical foundation for future investigations on the relationship between m7G modification-related genes, immunity, and drug sensitivity in LUSC.

Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer.

DNA double-strand breaks (DSBs) are the most lethal DNA damages which lead to severe genome instability. Phosphorylation is one of the most important protein post-translation modifications involved in DSBs repair regulation. Kinases and phosphatases play coordinating roles in DSB repair by phosphorylating and dephosphorylating various proteins. Recent research has shed light on the importance of maintaining a balance between kinase and phosphatase activities in DSB repair. The interplay between kinases and phosphatases plays an important role in regulating DNA-repair processes, and alterations in their activity can lead to genomic instability and disease. Therefore, study on the function of kinases and phosphatases in DSBs repair is essential for understanding their roles in cancer development and therapeutics. In this review, we summarize the current knowledge of kinases and phosphatases in DSBs repair regulation and highlight the advancements in the development of cancer therapies targeting kinases or phosphatases in DSBs repair pathways. In conclusion, understanding the balance of kinase and phosphatase activities in DSBs repair provides opportunities for the development of novel cancer therapeutics.

DNA Damage and Its Role in Cancer Therapeutics.

DNA damage is a double-edged sword in cancer cells. On the one hand, DNA damage exacerbates gene mutation frequency and cancer risk. Mutations in key DNA repair genes, such as breast cancer 1 (BRCA1) and/or breast cancer 2 (BRCA2), induce genomic instability and promote tumorigenesis. On the other hand, the induction of DNA damage using chemical reagents or radiation kills cancer cells effectively. Cancer-burdening mutations in key DNA repair-related genes imply relatively high sensitivity to chemotherapy or radiotherapy because of reduced DNA repair efficiency. Therefore, designing specific inhibitors targeting key enzymes in the DNA repair pathway is an effective way to induce synthetic lethality with chemotherapy or radiotherapy in cancer therapeutics. This study reviews the general pathways involved in DNA repair in cancer cells and the potential proteins that could be targeted for cancer therapeutics.

Enhanced catalytic activity and stability of composite of cellulose film and nano zero-valent iron on Juncus effusus for activating peroxydisulfate to degrade Rhodamine B dye.

In this study, a novel peroxydisulfate (PDS) activator (CF-nZVI-JE) was prepared via in-situ loading nano zero-valent iron (nZVI) on Juncus effusus (JE) followed with wrapping a layer of cellulose film (CF). The CF-nZVI-JE had the same 3D structure as the JE, being easy to separate from aqueous solution. The loaded nZVI existed single nanoparticles with a size of 60-100 nm except chain-type agglomeration of nanoparticles due to the stabilization of JE fibers. The activation performance of the CF-nZVI-JE for PDS was evaluated with Rhodamine B (Rh B) as a representative pollutant. Under the optimal activating conditions, the degradation rate of Rh B reached 99% within 30 min in the CF-nZVI-JE/PDS system. After five cycles, the degradation rate of Rh B was still over 85%, suggesting that the CF-nZVI-JE had good reusability. More interestingly, SO4·- and ·OH radicals were simultaneously detected in the CF-nZVI-JE/PDS system, but only SO4·- existed in the JE-ZVI/PDS system, suggesting the different activation mechanism. Meanwhile, the introduction of CF not only facilitated to the mineralization of Rh B but also significantly reduced the release amount of iron ions. Hence, the CF-nZVI-JE can be employed as a promising PDS activator for the treatment of organic wastewater.

Cytochrome P450 Transcriptional Regulation by Testis-Specific Y-Encoded-Like Protein: Identification of Novel Upstream Transcription Factors.

Cytochrome P450s (CYPs) display significant inter-individual variation in expression, much of which remains unexplained by known CYP single-nucleotide polymorphisms (SNPs). Testis-specific Y-encoded-like proteins (TSPYLs) are transcriptional regulators for several drug-metabolizing CYPs including CYP3A4 However, transcription factors (TFs) that might influence CYP expression through an effect on TSPYL expression are unknown. Therefore, we studied regulators of TSPYL expression in hepatic cell lines and their possible SNP-dependent variation. Specifically, we identified candidate TFs that might influence TSPYL expression using the ENCODE ChIPseq database. Subsequently, the expression of TSPYL1/2/4 as well as that of selected CYP targets for TSPYL regulation were assayed in hepatic cell lines before and after knockdown of TFs that might influence CYP expression through TSPYL-dependent mechanisms. Those results were confirmed by studies of TF binding to TSPYL1/2/4 gene promoter regions. In hepatic cell lines, knockdown of the REST and ZBTB7A TFs resulted in decreased TSPYL1 and TSPYL4 expression and increased CYP3A4 expression, changes reversed by TSPYL1/4 overexpression. Potential binding sites for REST and ZBTB7A on the promoters of TSPYL1 and TSPYL4 were confirmed by chromatin immunoprecipitation. Finally, common SNP variants in upstream binding sites on the TSPYL1/4 promoters were identified and luciferase reporter constructs confirmed SNP-dependent modulation of TSPYL1/4 gene transcription. In summary, we identified REST and ZBTB7A as regulators of the expression of TSPYL genes which themselves can contribute to regulation of CYP expression and-potentially-of drug metabolism. SNP-dependent modulation of TSPYL transcription may contribute to individual variation in both CYP expression and-downstream-drug response phenotypes. SIGNIFICANCE STATEMENT: Testis-specific Y-encoded-like proteins (TSPYLs) are transcriptional regulators of cytochrome P450 (CYP) gene expression. Here, we report that variation in TSPYL expression as a result of the effects of genetically regulated TSPYL transcription factors is an additional factor that could result in downstream variation in CYP expression and potentially, as a result, variation in drug biotransformation.

Testis- specific Y-encoded- like protein 1 and cholesterol metabolism: Regulation of CYP1B1 expression through Wnt signaling.

The cytochromes P450 (CYPs) represent a large gene superfamily that plays an important role in the metabolism of both exogenous and endogenous compounds. We have reported that the testis-specific Y-encoded-like proteins (TSPYLs) are novel CYP gene transcriptional regulators. However, little is known of mechanism(s) by which TSPYLs regulate CYP expression or the functional consequences of that regulation. The TSPYL gene family includes six members, TSPYL1 to TSPYL6. However, TSPYL3 is a pseudogene, TSPYL5 is only known to regulates the expression of CYP19A1, and TSPYL6 is expressed exclusively in the testis. Therefore, TSPYL 1, 2 and 4 were included in the present study. To better understand how TSPYL1, 2, and 4 might influence CYP expression, we performed a series of pull-downs and mass spectrometric analyses. Panther pathway analysis of the 2272 pulled down proteins for all 3 TSPYL isoforms showed that the top five pathways were the Wnt signaling pathway, the Integrin signaling pathway, the Gonadotropin releasing hormone receptor pathway, the Angiogenesis pathway and Inflammation mediated by chemokines and cytokines. Specifically, we observed that 177 Wnt signaling pathway proteins were pulled down with the TSPYLs. Subsequent luciferase assays showed that TSPYL1 knockdown had a greater effect on the activation of Wnt signaling than did TSPYL2 or TSPYL4 knockdown. Therefore, in subsequent experiments, we focused our attention on TSPYL1. HepaRG cell qRT-PCR showed that TSPYL1 regulated the expression of CYPs involved in cholesterol-metabolism such as CYP1B1 and CYP7A1. Furthermore, TSPYL1 and ß-catenin regulated CYP1B1 expression in opposite directions and TSPYL1 appeared to regulate CYP1B1 expression by blocking ß-catenin binding to the TCF7L2 transcription factor on the CYP1B1 promoter. In ß-catenin and TSPYL1 double knockdown cells, CYP1B1 expression and the generation of CYP1B1 downstream metabolites such as 20-HETE could be restored. Finally, we observed that TSPYL1 expression was associated with plasma cholesterol levels and BMI during previous clinical studies of obesity. In conclusion, this series of experiments has revealed a novel mechanism for regulation of the expression of cholesterol-metabolizing CYPs, particularly CYP1B1, by TSPYL1 via Wnt/ß-catenin signaling, raising the possibility that TSPYL1 might represent a molecular target for influencing cholesterol homeostasis.

Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment.

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders. IMPLICATIONS: Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Sulforaphane Upregulates Cultured Mouse Astrocytic Aquaporin-4 Expression through p38 MAPK Pathway.

Protein misfolding and/or aggregation are common pathological features associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson disease (PD). Abnormal protein aggregation may be caused by misfolding of the protein and/or dysfunction of the protein clearance system. Recent studies have demonstrated that the specific water channel protein, aquaporin-4 (AQP4), plays a role in the pathogenesis of neurodegenerative diseases involving protein clearance system. In this study, we aimed to investigate the role of sulforaphane (SFN) in the upregulation of AQP4 expression, along with its underlying mechanism using cultured mouse astrocytes as a model system. At low concentrations, SFN was found to increase cell proliferation and result in the activation of astrocytes. However, high SFN concentrations were found to suppress cell proliferation of astrocytes. In addition, our study found that a 1 µM concentration of SFN resulted in the upregulation of AQP4 expression and p38 MAPK phosphorylation in cultured mouse astrocytes. Moreover, we demonstrated that the upregulation of AQP4 expression was significantly attenuated when cells were pretreated with SB203580, a p38 MAPK inhibitor. In conclusion, our findings from this study revealed that SFN exerts hormesis effect on cultured mouse astrocytes and can upregulate astrocytic AQP4 expression by targeting the p38 MAPK pathway.

Kaiso phosphorylation at threonine 606 leads to its accumulation in the cytoplasm, reducing its transcriptional repression of the tumour suppressor CDH1.

It is well known that the Kaiso protein (encoded by the ZBTB33 gene) is a transcription factor, and Kaiso-P120ctn [P120 catenin (CTNND1)] interaction increases the translocation of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalisation are far from clear. Here, we reported that RAC-alpha serine/threonine-protein kinase (AKT1) could phosphorylate threonine residue 606 (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The T606-phosphorylated Kaiso (pT606-Kaiso) could directly bind to 14-3-3 family proteins, and depletion of T606 phosphorylation by T606A mutation abolished most of the Kaiso-14-3-3 binding. In addition, the Kaiso-P120ctn interaction was essential for pT606-Kaiso accumulation in the cytoplasm. Notably, enforced stratifin (14-3-3σ; SFN) overexpression could increase pT606-Kaiso accumulation in the cytoplasm and de-repress the transcription of Kaiso target gene cadherin 1 (CDH1), which is a tumour suppressor. Decreased amounts of both pT606-Kaiso and CDH1 proteins were frequently observed in human gastric cancer tissues compared to paired normal controls. The mRNA levels of 14-3-3σ and Kaiso target gene CDH1 showed highly significant positive correlations in both human normal tissues and cancer cell lines by bioinformatics analyses. Furthermore, Kaiso T606A mutant (unable to be phosphorylated) significantly increased the migration and invasion of cancer cells in vitro and promoted the growth of these cells in vivo. In conclusion, Kaiso could be phosphorylated at T606 by AKT1 and pT606-Kaiso accumulates in the cytoplasm through binding to 14-3-3/P120ctn, which de-represses the Kaiso target gene CDH1 in normal tissues. Decreased Kaiso phosphorylation might contribute to the development of gastrointestinal cancer. The status of Kaiso phosphorylation is a determinant factor for the role of Kaiso in the development of cancer.

Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer.

Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.

ASTE1 promotes shieldin-complex-mediated DNA repair by attenuating end resection.

The shieldin complex functions as the downstream effector of 53BP1-RIF1 to promote DNA double-strand break end-joining by restricting end resection. The SHLD2 subunit binds to single-stranded DNA ends and blocks end resection through OB-fold domains. Besides blocking end resection, it is unclear how the shieldin complex processes SHLD2-bound single-stranded DNA and promotes non-homologous end-joining. Here, we identify a downstream effector of the shieldin complex, ASTE1, as a structure-specific DNA endonuclease that specifically cleaves single-stranded DNA and 3' overhang DNA. ASTE1 localizes to DNA damage sites in a shieldin-dependent manner. Loss of ASTE1 impairs non-homologous end-joining, leads to hyper-resection and causes defective immunoglobulin class switch recombination. ASTE1 deficiency also causes resistance to poly(ADP-ribose) polymerase inhibitors in BRCA1-deficient cells owing to restoration of homologous recombination. These findings suggest that ASTE1-mediated 3' single-stranded DNA end cleavage contributes to the control of DSB repair choice by 53BP1, RIF1 and shieldin.

Establishment and characterization of immortalized human breast cancer cell lines from breast cancer patient-derived xenografts (PDX).

The application of patient-derived xenografts (PDX) in drug screening and testing is a costly and time-consuming endeavor. While cell lines permit extensive mechanistic studies, many human breast cancer cell lines lack patient characteristics and clinical treatment information. Establishing cell lines that retain patient's genetic and drug response information would enable greater drug screening and mechanistic studies. Therefore, we utilized breast cancer PDX from the Mayo Breast Cancer Genome Guided Therapy Study (BEAUTY) to establish two immortalized, genomically unique breast cancer cell lines. Through extensive genetic and therapeutic testing, the cell lines were found to retain the same clinical subtype, major somatic alterations, and drug response phenotypes as their corresponding PDX and patient tumor. Our findings demonstrate PDX can be utilized to develop immortalized breast cancer cell lines and provide a valuable tool for understanding the molecular mechanism of drug resistance and exploring novel treatment strategies.

ZNF423 modulates the AMP-activated protein kinase pathway and metformin response in a single nucleotide polymorphisms, estrogen and selective estrogen receptor modulator dependent fashion.

OBJECTIVES: We previously discovered that the single nucleotide polymorphisms (SNP) rs9940645 in the ZNF423 gene regulate ZNF423 expression and serve as a potential biomarker for response to selective estrogen receptor modulators (SERMs). Here we explored pathways involved in ZNF423-mediated SERMs response and drugs that potentially sensitize SERMs. METHODS: RNA sequencing and label-free quantitative proteomics were performed to identify genes and pathways that are regulated by ZNF423 and the ZNF423 SNP. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to metformin. RESULTS: We identified ribosome and AMP-activated protein kinase (AMPK) signaling as potential pathways regulated by ZNF423 or ZNF423 rs9940645 SNP. Moreover, using clustered regularly interspaced short palindromic repeats/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to metformin, either alone or in the combination of tamoxifen, were observed in both cell culture and the mouse xenograft model. CONCLUSIONS: We found that AMPK signaling is modulated by the ZNF423 rs9940645 SNP in estrogen and SERM-dependent fashion. The ZNF423 rs9940645 SNP affects metformin response in breast cancer and could be a potential biomarker for tailoring the metformin treatment.

USP13 regulates the replication stress response by deubiquitinating TopBP1.

The DNA replication stress-induced checkpoint activated through the TopBP1-ATR axis is important for maintaining genomic stability. However, the regulation of TopBP1 in DNA-damage responses remains unclear. In this study, we identify the deubiquitinating enzyme (DUB) USP13 as an important regulator of TopBP1. Mechanistically, USP13 binds to TopBP1 and stabilizes TopBP1 by deubiquitination. Depletion of USP13 impedes ATR activation and hypersensitizes cells to replication stress-inducing agents. Furthermore, high USP13 expression enhances the replication stress response, promotes cancer cell chemoresistance, and is correlated with poor prognosis of cancer patients. Overall, these findings suggest that USP13 is a novel deubiquitinating enzyme for TopBP1 and coordinates the replication stress response.

ERICH3: vesicular association and antidepressant treatment response.

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.

Variable Light Condition Improves Root Distribution Shallowness and P Uptake of Soybean in Maize/Soybean Relay Strip Intercropping System.

In this study, soybean root distribution in an inter-cropping system was influenced by various environmental and biotic cues. However, it is still unknown how root development and distribution in inter-cropping responds to aboveground light conditions. Herein, soybeans were inter- and monocropped with P (phosphorus) treatments of 0 and 20 kg P ha yr-1 (P0 and P20, respectively) in field experiment over 4 years. In 2019, a pot experiment was conducted as the supplement to the field experiment. Shade from sowing to V5 (Five trifoliolates unroll) and light (SL) was used to imitate the light condition of soybeans in a relay trip inter-cropping system, while light then shade from V5 to maturity (LS) was used to imitate the light condition of soybeans when monocropped. Compared to monocropping, P uptake and root distribution in the upper 0-15 cm soil layer increased when inter-cropped. Inter-cropped soybeans suffered serious shade by maize during a common-growth period, which resulted in the inhibition of primary root growth and a modified auxin synthesis center and response. During the solo-existing period, plant photosynthetic capacity and sucrose accumulation increased under ameliorated light in SL (shade-light). Increased light during the reproductive stage significantly decreased leaf P concentration in SL under both P-sufficient and P-deficient conditions. Transcripts of a P starvation response gene (GmPHR25) in leaves and genes (GmEXPB2) involved in root growth were upregulated by ameliorated light during the reproductive stage. Furthermore, during the reproductive stage, more light interception increased the auxin concentration and expression of GmYUCCA14 (encoding the auxin synthesis) and GmTIR1C (auxin receptor) in roots. Across the field and pot experiments, increased lateral root growth and shallower root distribution were associated with inhibited primary root growth during the seedling stage and ameliorated light conditions in the reproductive stage. Consequently, this improved topsoil foraging and P uptake of inter-cropped soybeans. It is suggested that the various light conditions (shade-light) mediating leaf P status and sucrose transport can regulate auxin synthesis and respond to root formation and distribution.

Functional genomics based on germline genome-wide association studies of endocrine therapy for breast cancer.

Breast cancer is the most common invasive cancer in women worldwide. Functional follow-up of breast cancer genome-wide association studies has led to the discovery of genes that regulate endocrine therapy response in a SNP- and drug-dependent manner. Here, we will present four examples in which functional genomic studies from breast cancer clinical trials led to novel pharmacogenomic insights and molecular mechanisms of selective estrogen receptor modulators and aromatase inhibitors. The approach utilized for studying genetic variability described in this review offers substantial potential for meaningful discoveries that move the field toward precision medicine for patients.

Osteogenic differentiation of rat bone mesenchymal stem cells modulated by MiR-186 via SIRT6.

AIMS: Osteoporosis has been known to generally result from an imbalance between bone formation and resorption. Osteogenesis is the process of differentiation of mesenchymal stem cells (MSCs) into osteoblasts. Sirtuin6 (SIRT6) has been reported to mediate osteogenic differentiation (OD) in rat bone MSCs (rBMSCs). The present study aimed to assess the influence of microRNA miR-186 on the proliferation and OD potential of rBMSCs. MAIN METHODS: OD was performed and evaluated through Alizarin red S staining, alkaline phosphatase (ALP) activity, and specific marker expression. KEY FINDINGS: miR-186 downregulation was observed during OD. rBMSCs with miR-186 overexpression were generated via transfection. Compared with vehicle negative controls, miR-186 upregulation significantly repressed rBMSCs' OD, as evidenced by a reduced ALP activity and decreased mRNA levels of osteogenic markers [osteocalcin, Runx2, BSP, and ALP]. Furthermore, bioinformatic prediction and dual-luciferase reporter assay demonstrated that miR-186 targeted SIRT6 3'-UTR for silencing. SIRT6 overexpression reversed the inhibitory effect of miR-186 on the OD of rBMSCs. Additionally, further examination showed that the activation of nuclear factor-kappa B (NFκB) pathway was involved in the miR-186/SIRT6 signal axis, and phorbol 12-myristate 13-acetate, a NFκB activator, also inhibited the OD of rBMSCs. SIGNIFICANCE: The present study results may demonstrate a novel mechanism of rBMSCs OD via miR-186-SIRT6 interaction.