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PubMed2005

Representational difference analysis as a tool in the search for new tumor suppressor genes.

The recognition of a homozygous deletion of genetic material in a tumor genome has been instrumental in several tumor suppressor gene searches. The representational difference analysis (RDA) allows one to identify homozygous deletions even from among the high background of allelic losses that is typical for most cancers. RDA is a polymerase chain reaction (PCR)-based subtractive hybridization method. Two major obstacles to successful enrichment of target sequences from complex genomes were circumvented by RDA. Incomplete reassociation of complex DNA populations is overcome by using representative subpopulations of the tester and driver genomes. In addition, reiterated hybridization, selection, and amplification of the difference products introduces a kinetic component in the enrichment of target sequences. RDA thus enables the identification of homozygous deletions as small as 100 kilobases. Here, we provide a detailed protocol of the RDA procedure, including reflections on frequently encountered technical problems and on the particulars of its application in cancer.

Base Sequence↗

PubMed2026

Integrated transcriptomic and functional characterization of Claudin-1 reveals its oncogenic and immunomodulatory roles in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, driven by its invasive nature and lack of effective biomarkers. Disruption of the epithelial barrier, mediated by tight junction components, is a critical yet underexplored contributor to PDAC progression. Claudins, integral regulators of tight junction integrity, display altered expression across cancers, but their prognostic and immunomodulatory roles in PDAC remain unclear. We performed an integrative analysis of 177 RNA-Seq datasets from TCGA and GTEx to characterize Claudin family alterations in PDAC. Differential expression, copy number variation, methylation, and co-expression networks were analyzed alongside clinical and survival data. Prognostic significance was assessed using Kaplan - Meier and Cox regression analyses, while immune cell infiltration was examined using deconvolution algorithms. Functional validation of Claudin-1 was conducted in Capan-1 cells using CRISPR/Cas9 knockout, followed by proliferation, wound-healing, and Western blot assays. Ten Claudin genes were significantly dysregulated, with Claudin-1 and Claudin-4 frequently amplified and associated with advanced stage and poor survival. High Claudin-1 expression correlated with reduced immune infiltration, indicating an immune-excluded phenotype characterized by immune cells retained in the tumor stroma but largely absent from the tumor parenchyma. Claudin-1 knockout markedly inhibited proliferation, migration, and EMT, evidenced by downregulation of Snail and Slug and restoration of E-cadherin expression. This integrative transcriptomic and functional study identifies Claudin-1 as a key driver of PDAC aggressiveness and immune modulation. These findings establish Claudin-1 as a promising prognostic biomarker and therapeutic target for restoring epithelial integrity and counteracting immune evasion in pancreatic cancer.

Humans↗

PubMed2026

Integrative single-cell and genomic analysis reveals NMB as a driver of metastatic adaptation in esophageal squamous cell carcinoma via metabolic rewiring and immune evasion.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has high mortality, and metastasis is the leading cause of patient death. Neuromedin B (NMB) promotes tumor development in various cancers, yet its role in ESCC metastasis remains unclear. METHODS: We integrated single-cell transcriptomic data from matched primary and metastatic ESCC lesions (GSE309392) with bulk transcriptomic cohorts from TCGA and GSE53624. In silico gene perturbation, ligand-receptor communication analysis, and single-cell prognostic model construction were performed, followed by functional validation through siRNA-mediated NMB knockdown in TE-1 and KYSE30 cell lines. RESULTS: NMB was identified as a key gene enriched in metastatic ESCC lesions, and its high expression was associated with coordinated upregulation of oxidative phosphorylation pathway genes and aldo-keto reductase family antioxidant enzymes (AKR1C1, AKR1C2, AKR1B10). Genomic analysis revealed that NMB-high tumors carried a higher clonal mutation burden and a markedly increased frequency of NFE2L2 activating mutations (23% vs. 8%, P = 0.04). In silico knockout and correlation analysis identified AKR1C1 as a downstream effector of NMB. NMB expression was negatively correlated with CD8+ T cell and activated NK cell infiltration. CellChat analysis revealed communication between NMB-positive cells and monocytes via the TGM2-ADGRG1 axis, and specifically detected IFNG signaling. In the single-cell prognostic model, NMB-positive cells accounted for 50% of the high-risk group but only 20% of the low-risk group. TCGA-based survival analysis demonstrated that high NMB expression was associated with shorter overall survival (HR = 2.98, P = 0.03). In vitro NMB-targeted RNA interference markedly inhibited proliferation, colony formation, and migration in TE-1 and KYSE30 cells. CMap screening identified the endothelin-PDE5-cGMP axis as a potential therapeutic target. CONCLUSION: NMB serves as a key driver of metastatic adaptation in ESCC, conferring a survival advantage to tumor cells during metastatic colonization through genomic evolution and immune remodeling, with metabolic adaptation as a downstream consequence of genomic alterations.

NMB↗

PubMed1997

Association of Stein-Leventhal syndrome with the incidence of postmenopausal breast carcinoma in a large prospective study of women in Iowa.

BACKGROUND: The Stein-Leventhal syndrome (SLS), first described in 1935, is characterized by infertility, hyperandrogenization, and obesity. Because this phenotype represents an aggregation of risk factors for postmenopausal breast carcinoma, and because in general, a hormonal imbalance underlies the disorder, the authors examined the association between self-reported SLS and breast carcinoma incidence in a cohort of 34,835 cancer-free women assembled in 1986 and followed through 1992. METHODS: All participants were between the ages of 55 and 69 and held a valid Iowa driver's license. A total of 472 women in the cohort (1.35%) reported a history of SLS at baseline. Incident cases of breast carcinoma were identified annually using the State Health Registry of Iowa. Data were analyzed using Cox proportional hazards regression. RESULTS: During the follow-up period, there were 883 incident breast carcinomas, 14 among women reporting a history of SLS. Women with SLS were more likely than women without SLS to report fertility problems and menstrual irregularities, but there were no significant differences observed regarding body mass index (BMI). Although women with SLS were 1.8 times as likely to report benign breast disease than women without SLS (P < 0.01), they were not more likely to develop breast carcinoma (relative risk [RR] = 1.2; 95% confidence interval [CI] = 0.7-2). Adjustment for age at menarche, age at menopause, parity, oral contraceptive use, BMI, waist-to-hip ratio, and family history of breast carcinoma lowered the RR to 1 (95% CI = 0.6-1.9. CONCLUSIONS: Despite the high risk profiles of some women with SLS, these results do not suggest that the syndrome per se is associated with an increased risk of postmenopausal breast carcinoma.

Aged↗

PubMed2004

The changing costs of radiation treatment for early prostate cancer in Ontario: a comparison between conventional and conformal external beam radiotherapy.

PURPOSE: Prostate cancer represents a large part of the workload for radiation oncology departments in Canada. Recent evidence suggests that conformal external beam radiotherapy improves results. The planning and treatment process for conformal patients requires a greater amount of resources that are in short supply in Ontario. An understanding of these differences is important to provide an accurate estimate of future radiation needs of the province. These differences can be quantified in a cost model that portrays the direct costs of delivering external beam radiotherapy in Ontario. With a developed cost model, a prospective direct cost comparison between standard four field external beam radiotherapy versus conformal radiotherapy in early stage prostate carcinoma was designed. METHODS: Activity based costing has been used to create a model of radiotherapy related costs for prostate cancer. A process map was developed which separated the process in five activities for conventional radiotherapy and six activities for dose escalated conformal radiotherapy. Time was recognized as the important cost driver within each activity. The time required for pre-treatment preparation (CT planning, dosimetry, simulation, and other preparatory work) and actual treatment times were collected prospectively. Treatment times were collected in 414 patients. The annual costs of capital equipment purchase costs and specialized construction of hospital space for radiotherapy equipment were amortized using a 6% discount rate plus the cost of annual maintenance. Indirect costs were not included in this cost analysis. RESULTS: An activity based costing model using time as the primary cost driver reflects the additional costs of conformal over conventional external beam radiotherapy. The costs of single phase and double phase six field conformal therapy with 42 fractions delivered was 7867 Canadian dollars and 8227 Canadian dollars per patient. Four field single phase conformal therapy with 28 fractions costs 5723 Canadian dollars. The cost of conventional radiotherapy over 33 fractions was 3068 Canadian dollars. The majority of the cost differences arose from the cost of the additional time needed for treatment per day as well as the extra fractions per patient when compared to conventionally treated patients. The average treatment times per fraction for six field conformal, four field conformal and four field conventional have the median times of 22.72, 20.63 and 11.07 minutes respectively. Planning costs for conformal radiotherapy were up to three times the cost of conventional therapy. CONCLUSIONS: The direct costs of dose escalated conformal external beam radiotherapy are over 2.5 times that of conventional external beam radiotherapy for early stage prostate cancer. These direct costs are a reflection of the additional capital and human resources needed to provide state-of-the-art radiation therapy in the province of Ontario. Planning for radiation oncology needs should consider the additional costs of conformal external beam radiotherapy.

Costs and Cost Analysis↗

PubMed1988

Occupation and risk of cancer of the lower urinary tract among men. A case-control study.

Data from a hospital-based matched case-control study with 531 male pairs were analyzed for risks of cancer of the lower urinary tract associated with previous employment and particular occupational exposures. Statistically significant odds ratios were obtained for ever-employment as mining workers (2.0), turners (2.3), tailors (2.7), truck drivers (1.8), locomotive drivers (3.0) and janitors (3.5), whereas odds ratios of 3.0 or more, found for rubber and plastics workers, printing workers, gas workers, artists and chemists were not statistically significant. When adjusted for smoking, there was a trend toward increasing relative risks with increasing duration of employment as truck drivers and as turners, and relative risks rose 3-fold for 30 or more years of employment. With regard to a priori high-risk industries, ever-employment in the rubber, plastics and synthetics, dyestuff and paints, mining, and printing industries and secondary processing was associated with significantly higher relative risks, and a statistically significant trend in risk with increasing duration of employment was found for the first 3 industries mentioned. With regard to job-related exposures to specified substances, the relative risks observed for increasing duration of exposure suggest that exposures to petroleum, oils, chromium/chromate, spray paints, and zinc, which correspond to exposures involved in the occupations showing a higher relative risk in this study, are associated with a higher risk for cancer of the lower urinary tract.

Germany, West↗

PubMed2026

Interplay between DNA and RNA methylation shapes cancer cell plasticity.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Humans↗

PubMed1992

Risk factors for surgery for prostatic hypertrophy.

The purpose of this case-control study was to evaluate potential risk factors for prostatic hypertrophy. The cases were 910 residents of Rhode Island who had a partial or total prostatectomy that was not related to cancer in the years 1985-1987. The controls were 2,003 members of the source population who were selected from a list of holders of Rhode Island driver's licenses or a roster of older Americans compiled by the Health Care Financing Administration. Cases and controls were interviewed by telephone. The risk of prostatic hypertrophy was elevated in Jewish men compared with Protestants and Catholics and in blacks compared with whites. Risk was reduced in ever-married compared with never-married men, in men who had left school at age 16 years or more compared with those who had left earlier, and in relatively tall or relatively heavy men. Coffee drinking and cigarette smoking were inversely but only weakly related to prostatic hypertrophy. There was a relatively strong, although irregular, inverse relation of beer drinking to prostatic hypertrophy. The associations of spirits and wine consumption with prostatic hypertrophy were weak.

Age Factors↗

PubMed2026

Molecular and Clinical Determinants of Targeted Therapy Treatment in Biliary Tract Cancer.

PURPOSE: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer; however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require further characterization. EXPERIMENTAL DESIGN: We analyzed a prospectively maintained cohort of 1,254 patients with histologically confirmed biliary tract cancer who underwent molecular profiling using an FDA-authorized targeted next-generation sequencing (NGS) assay. We defined actionable alterations across anatomic subsets, compared outcomes with targeted therapy versus cytotoxics, and evaluated genomic correlates of resistance using longitudinal samples. RESULTS: Overall, 59% of patients harbored at least one OncoKB alteration, and 32.2% (intrahepatic 40%, extrahepatic 15%, and gallbladder 22%) had a level 1/2 alteration. Emerging targets included KRAS alterations (17%), MTAP deletions (12.8%), MDM2 amplification (6.5%), and MET amplification (1.5%). Targeted therapy was associated with improved progression-free survival but not overall survival. Co-occurring TP53/RAS pathway and SMAD4 alterations were associated with inferior outcomes in IDH1/FGFR2-and ERBB2-driven tumors, respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumors, whereas IDH-, FGFR-, BRAF-, and NTRK-driven tumors retained the primary oncogenic driver. Acquired resistance was associated with alterations in RAS, MEK, MET, MYC, and CDKN2A. CONCLUSIONS: This comprehensive molecular profiling study illustrates the real-world utility and limitations of targeted NGS of biliary tract cancer and affirms the use of precision medicine in patients with these diseases. Genomic heterogeneity and therapeutic resistance observed in this study has the potential to inform ongoing drug development efforts for biliary tract cancer.

Humans↗

PubMed1993

Occupational risk factors for lung cancer among nonsmoking women: a case-control study in Missouri (United States).

Occupationally related risk of lung cancer among women and among nonsmokers has not been widely studied. A recently conducted population-based, case-control study in Missouri (United States) provided the opportunity to evaluate risk of lung cancer associated with several occupational factors. Incident cases (n = 429) were identified through the Missouri Cancer Registry for the period 1986 through 1991, and included 294 lifetime nonsmokers and 135 ex-smokers who had stopped at least 15 years prior to diagnosis or had smoked for less than one pack-year. Controls (n = 1,021) were selected through driver's license and Medicare files. Risk was elevated among women exposed to asbestos (ever: odds ratio [OR] = 3.5, 95 percent confidence interval [CI] = 1.2-10.0; > 9 yrs: OR = 4.6, CI = 1.1-19.2) and pesticides (ever: OR = 2.4, CI = 1.1-5.6; > 17.5 yrs: OR = 2.4, CI = 0.8-7.0). Risk also was elevated among dry cleaning workers (ever: OR = 1.8, CI = 1.1-3.0; > 1.125 yrs: OR = 2.9, CI = 1.5-5.4). Occupational risks for lung cancer among women merit further study.

Adult↗

PubMed1989

Occupational cancer mortality in Illinois white and black males, 1979-1984, for seven cancer sites.

A death certificate mortality odds ratio study of seven cancer sites was conducted by using 1979-1984 data on Illinois deaths in white and black males. Cancer sites selected include stomach, pancreas, lung, prostate, bladder, brain, and non-Hodgkin's lymphomas. This surveillance study was undertaken to detect occupational associations that might suggest further avenues of research. Some of the occupations and industries found to have elevated cancer risks and that are consistent with previous studies include: brickmasons and stonemasons (stomach); metal workers (pancreas, lung); photoengravers and lithographers (pancreas); butchers (lung); locomotive operators and truck drivers (lung); farmers (prostate, brain, non-Hodgkin's lymphoma); mechanics and repairers, especially auto mechanics (prostate); physicians (brain); glass products manufacturing workers (brain); and communications industry (brain) and chemical plant workers (non-Hodgkin's lymphomas). It was also noted that for black males, the death certificate occupational data are of limited usefulness due to the high percentage of missing or inexact information. The Division of Vital Records in the State of Illinois should make an effort to improve the reporting of this data through additional training of the funeral directors and hospital clerks who collect this information and by follow-up of incomplete or missing data.

Adult↗

PubMed2026

A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.

Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.

Humans↗

PubMed1997

Communicating with cancer patients in Saudi Arabia.

The following factors are relevant to the communication problems that exist in this country: 1. CULTURAL ASPECTS: The impression is that patients here cope better with terminal illness at home than do patients elsewhere. The extended family, with its strong ties, and the strong Islamic faith that encourages its members to provide for parents and children in case of need mean that any input by health professionals is magnified by the family in the care of the patient. At first, it was uncertain if foreign health professionals would be accepted into Saudi homes (which are intensely private and protected for the family) for the purpose of caring for patients. This has proved unfounded. Hospitality is a very important part of Saudi society; nurses and doctors are welcomed and respected. Much of this success is due to the use of Saudi men as drivers and translators. These people provide 24-hour service, act as social workers assessing the needs of the family, and are the link between the patient and family, the nurse, and the doctor. 2. "CURE" OR "PALLIATION": The emphasis for cancer patients in Saudi Arabia is still on "curative treatment," even after any realistic hope of a cure is gone. The problem this causes is compounded by many patients being excluded from the decision-making process. Decisions made by the family may not always reflect the patient's wishes. Greater communication is needed to guide treatment decisions. 3. TRUTH-TELLING: Denying information of the patient's illness is probably more a historical than a cultural phenomenon. Similar attitudes prevailed until very recently in practically all other countries. In this very conservative country, people are committed to preserving Islamic culture in the face of Western technology. As medicine continues to demonstrate its effectiveness as well as its limitations, people will come to realize that the right of patients to know and understand their illness allows them to cope much better, and is compatible with the responsibility of the family to care for them. 4. WORK FORCE: The government employs 14,500 doctors, but only 12% are Saudi nationals. Nearly all the 33,000 nursing work force are expatriates. There is a constant turnover of expatriate staff. The commitment to continuing care with proper communication that is required for the whole of medicine is likely to be fully realized only when the majority of the workforce are Saudi nationals. 5. PRIMARY, SECONDARY, AND TERTIARY CARE SERVICES: The Kingdom is well served by a system of 174 public hospitals and numerous private clinics. However, for a patient with a chronic or terminal illness, continuing care, even in the community, tends to be provided by the hospital service; whereas the polyclinics and health centers seem to provide mainly crisis management. The aim should be to develop community care for chronic illness as part of the primary health care system. The impact of Western medicine on Saudi society has been dramatic and sudden, as evidenced by the high growth rate of the population. There is now widespread interest in matching the culture to the technology. Much of the drive to change the attitudes of both patients and health professionals comes from young Western-trained Saudi doctors, who are in the best position to merge the strengths of both cultures in this sensitive area.

Adaptation, Psychological↗

PubMed2026

Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.

Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity.

Humans↗

PubMed2002

Farnesyltransferase inhibitors: potential therapeutic for inflammatory breast cancer?

Inflammatory breast cancer (IBC) is an aggressive and poorly managed disease that accounts for up to 6% of new breast cancer cases in the United States annually. Recent preclinical findings suggest that IBC might be treated with farnesyltransferase inhibitors (FTIs), a novel class of experimental therapeutics that are currently in clinical trials. FTIs exhibit considerable selectivity and efficacy against tumors in preclinical models, and they have been well-tolerated in Phase I human trials. How FTIs target cancer cells has emerged as an important question, with the somewhat disappointing results from initial Phase II efficacy trials. FTI development was predicated on Ras inhibition but there is considerable evidence that other mechanisms are important for mediating the antineoplastic activities of these drugs. One important mediator that has emerged is RhoB, a small GTPase that is recruited by FTIs to trigger growth inhibition and apoptosis. Recently, van Golen and Merajver and their colleagues have demonstrated that FTIs will recruit RhoB to suppress IBC cell phenotypes or neoplastic transformation of human mammary epithelial cells by RhoC, a key oncogenic driver in IBC. A mechanistic implication of this study is that RhoB can interfere with RhoC-dependent signals required for neoplastic pathophysiology. Further preclinical and clinical investigations to test the potential therapeutic utility of FTIs for treating RhoC-driven breast cancers such as IBC would seem warranted.

Journal Article↗

PubMed2026

Genome-scale CRISPR screening uncovers SRSF6 as a target to sensitize hepatocellular carcinoma to radiotherapy.

BACKGROUND & AIMS: Radiotherapy confers clinical benefits to patients with hepatocellular carcinoma (HCC) across all stages, yet its clinical efficacy is limited by radioresistance. This study aimed to identify key regulators of HCC radiosensitivity through genome-wide functional screening. METHODS: A genome-wide CRISPR-Cas9 screen in Huh7 cells identified radiosensitivity regulators, with SRSF6 validated by siRNA knockdown and γ-H2AX assessment. Stable shRNA-mediated SRSF6 knockdown was established in Huh7 and HepG2 cells, followed by clonogenic, EdU incorporation, apoptosis, micronucleus, and comet assays. Mechanistically, RNA-seq, Western blotting, mRNA stability assays, RIP-qPCR, and RAD51 overexpression rescue assays were performed. The therapeutic potential of the SRSF6 inhibitor indacaterol was evaluated using MTS assays, HCC xenograft mouse models (BALB/c-nu/nu, n = 28), and HCC patient-derived organoids (PDOs) (n = 3). In addition, SRSF6 expression and its correlation with patient survival were analyzed using data from The Cancer Genome Atlas and a tissue microarray (n = 14 HCC and 14 paired adjacent non-tumorous liver samples). RESULTS: We identified the RNA-binding protein SRSF6 as a driver of HCC radioresistance. SRSF6 depletion enhanced the radiosensitivity of HCC cells (p <0.05-0.0001) by post-transcriptionally destabilizing the mRNAs of critical DNA repair genes (p <0.05-0.0001), thereby impairing radiation-induced DNA damage repair. The radiosensitizing effect of SRSF6 depletion was partially abrogated by ectopic overexpression of the core DNA repair protein RAD51 (p <0.05-0.001). Indacaterol exhibited cytotoxic effects on HCC cells (p <0.05-0.0001) and enhanced the antitumor efficacy of radiation in vivo (p <0.05-0.0001), as further validated across multiple HCC patient-derived organoids (p <0.05-0.0001). CONCLUSIONS: SRSF6 is a key regulator of HCC radioresistance through its post-transcriptional control of DNA repair capacity, and represents a novel therapeutic target to sensitize HCC to radiotherapy. IMPACT AND IMPLICATIONS: In this study, we performed a genome-wide CRISPR-Cas9 knockout library screen to dissect the molecular determinants governing HCC radiosensitivity, and identified RNA-binding protein SRSF6 as a driver of HCC radioresistance. We demonstrate that SRSF6 depletion disrupts the post-transcriptional stability of key DNA repair gene mRNAs and enhances HCC radiosensitivity. These findings are important for radiation oncologists and translational researchers, as they identify SRSF6-dependent RNA regulation as a critical determinant of radiotherapy response in HCC. Practically, we show that the clinically approved bronchodilator indacaterol suppresses SRSF6 function and enhances the antitumor efficacy of radiotherapy, offering a readily repurposable pharmacological strategy to overcome radioresistance. These implications are based on preclinical evidence across multiple models; however, future clinical trials are needed to validate the safety and efficacy of indacaterol-based radiosensitization in patients with HCC.

DNA repair↗

PubMed2001

Analysis of differentially expressed genes in human hepatocellular carcinoma using suppression subtractive hybridization.

The genetic basis of hepatocellular carcinoma (HCC) has not yet been fully understood. Although various methods have been developed to detect differentially expressed genes in malignant diseases, efficient analysis from clinical specimens is generally difficult to perform due to the requirement of a large amount of samples. In the present study, we analysed differentially expressed genes with a small amount of human HCC samples using suppression subtractive hybridization (SSH). Total RNA were obtained from the hepatitis C virus-associated HCC and adjacent non-HCC liver tissues. cDNA was synthesized using modified RT-PCR, and then tester cDNA was ligated with 2 different kinds of adaptors and hybridized with an excess amount of driver cDNA. Tester specific cDNA was obtained by suppression PCR and the final PCR product was subcloned and sequenced. We identified 7 known genes (focal adhesion kinase, deleted in colon cancer, guanine binding inhibitory protein alpha, glutamine synthetase, ornithine aminotransferase, M130, and pepsinogen C) and 2 previously unknown genes as being overexpressed in HCC, and 1 gene (decorin) as suppressed in HCC. Quantitative analysis of gene expression using quantitative RT-PCR demonstrated the differential expression of these genes in the original and other HCC samples. These findings demonstrated that it is possible to identify the previously unknown, differential gene expression from a small amount of clinical samples. Information about such alterations in gene expression could be useful for elucidating the genetic events in HCC pathogenesis, developing the new diagnostic markers, or determining novel therapeutic targets.

Amino Acid Sequence↗

PubMed2006

A prospective observational study of a cohort of outpatients with an acute medical event and reduced mobility: incidence of symptomatic thromboembolism and description of thromboprophylaxis practices.

OBJECTIVES: The study was performed to determine the incidence of symptomatic venous thromboembolism in outpatients with an acute medical event causing temporary reduced mobility. Risk factors for venous thromboembolism and thromboprophylaxis practices were also studied. DESIGN: This was a prospective, observational, multicentre, cohort study. SETTING: General practitioners randomly selected from a registry of 25,000 active representative doctors in France including eligible outpatients. SUBJECTS: Outpatients aged at least 40 years anticipated to have reduced mobility for at least 48 h due to an acute medical event were eligible. INTERVENTIONS: None required. MAIN OUTCOME MEASURES: Symptomatic deep-vein thrombosis and pulmonary embolism at 3 weeks were the main study end-points. RESULTS: Overall, 16,532 evaluable patients of mean age 71 years were recruited between October 2002 and June 2003 by 2895 doctors. The main acute medical events leading to reduced mobility were infection, acute rheumatism and falls without fracture. The incidence rates (95% confidence interval) of symptomatic deep-vein thrombosis and pulmonary embolism were 1% (0.84-1.14) and 0.20% (0.13-0.27) respectively. Venous insufficiency in legs, cancer, and a personal or family history of venous thromboembolism were independent risk factors for venous thromboembolism. Pharmacological thromboprophylaxis was initiated in 35.0% (n=5782) of the patients. The principal driver of prescription was a personal history of venous thromboembolism. CONCLUSIONS: The risk of symptomatic venous thromboembolism in outpatients with reduced mobility for medical reasons is close to that reported in medical and surgical inpatients. This risk and the potential need for thromboprophylaxis should be taken into account by primary care doctors.

Acute Disease↗