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At least 469 records · Page 26Linked to original sources
PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗
PubMed2026

Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.

While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.

CRISPR interference screening↗
PubMed1998

Cost analysis of palliative care for terminally ill cancer patients in the UK after switching from weak to strong opioids. Palliative Care Advisory Committee.

OBJECTIVE: We constructed a UK-based decision model of palliative care for terminally ill cancer patients who were switched from a weak to a strong opioid so that the expected direct healthcare costs in the UK could be estimated from the time a patient commenced a strong opioid until death. DESIGN: Decision analysis techniques were used to estimate the expected total direct healthcare cost per patient, stratified according to the first choice of strong opioid. The model was based on prescription data on 1975 terminally ill cancer patients who were on the Intercontinental Medical Statistics database, Mediplus (IMS Ltd, Middlesex, England). Resource-use data were obtained from published literature, a Delphi Panel and an advisory panel with expertise in palliative care. MAIN OUTCOME MEASURES AND RESULTS: The expected cost of managing terminally ill cancer patients after they switched from a weak to a strong opioid ranged from 2391 pounds sterling (Pounds) to 3701 Pounds at 1995/1996 prices, depending primarily on the patient's duration of survival. Sensitivity analyses showed that the cost could be as low as 1500 Pounds or as high as 6000 Pounds, depending on resource use (at 1995/1996 prices). The key cost drivers were: hospice care, hospitalisation, general practitioner (GP) consultations and specialist nurse visits. In contrast, neither the choice of opioid nor managing constipation impacted substantially on the expected cost. Approximately two-thirds of the expected total cost was incurred by the UK National Health Service (NHS), with the remainder incurred by voluntary and charitable sectors. Hospice care and hospitalisation collectively accounted for between 50 and 80% of the expected costs. Management of patients in the community by the primary healthcare team accounted for between 10 and 40% of the costs. The acquisition cost of opioids accounted for between 2 and 8% of the expected cost and discounting the cost of these drugs sold to hospitals did not impact substantially on the total expected costs. The use of other resources such as antiemetics, NSAIDS, antidepressants and gastrointestinal drugs accounted for up to 3% of the expected cost. CONCLUSION: The expected cost of palliative care in the UK healthcare setting ranged from approximately 2500 Pounds to 4000 Pounds (1500 Pounds to 6000 Pounds in the sensitivity analysis) depending on the length of survival after patients switch from weak to strong opioids. Since opioids account for only 2 to 8% of expected costs, factors other than economic issues, such as tolerability profile, patient preference and convenience of use, should form the basis of clinical decision-making between opioids with similar analgesic efficacy.

Analgesics, Opioid↗
PubMed1987

A case-control study of bladder cancer using city directories as a source of occupational data.

Commercial city directories, currently produced in 1,250 United States cities, potentially provide yearly information on occupation and employer for all city residents over age 18 years. To investigate the usefulness of these occupational data, the authors have conducted a case-control study of male bladder cancer mortality in Hamilton County, Ohio (which includes Cincinnati). A total of 731 bladder cancer cases who died during 1960-1982 were matched on age, sex, race, date-of-death, and residence at death to two controls per case. Risks of bladder cancer death were calculated by occupation, industry, and specific employer, using both city directories (multiple statements) and death certificates (single statement). Four companies showed a significant excess bladder cancer risk when using city directories. Only one would have been identified using death certificates, which ask for usual lifetime type of industry rather than a specific company name. Using city directories, significant positive associations were found between bladder cancer and occupation as an engineer, tailor, carpenter, furnace operator, blending machine operator, chemist, pressing machine operator, house cleaner, or salesman. For industry, the authors found significant positive associations for the textile, chemical, grain mill, foundry, petroleum, building service, entertainment, and advertising industries. A significant increase in risk for those with 20 or more years of employment was seen for those employed as truck drivers and furnace operators, or those employed in the railroad industry. A check of the validity of city directory data indicated that 77 per cent of the listings agreed with Social Security earnings reports for employer in any given year. One limitation of Hamilton County city directory data was the fairly large number of yearly listings without any occupational data (15 per cent for occupation, 36 per cent for employer). While city directory data do provide work history over time, unlike death certificates, such data are available only for years of residence in the city in question.

Death Certificates↗
PubMed2026

Genomic and epigenomic diversity of breast cancer across Western and MENA populations: implications for precision oncology.

Breast cancer is the most common malignancy in women worldwide and is increasingly recognized as a biologically diverse disease shaped by both molecular and ancestral context. Women from the Middle East and North Africa (MENA) populations, including Saudi Arabia, often present at a younger age and with more aggressive subtypes such as HER2-positive and triple-negative breast cancer (TNBC) compared with Western cohorts. These clinical patterns reflect a distinctive genomic background marked by high consanguinity, founder mutations in key susceptibility genes, and population-specific somatic alterations that are not fully captured in global reference datasets. This review brings together current evidence on somatic, germline, transcriptomic, and epigenomic diversity in breast cancer across Western and MENA populations, with a focus on Saudi cohorts. Drawing on a previously published systematic review of more than 2,500 MENA breast cancer cases, TP53 accounted for approximately 24% and PIK3CA for roughly 10% of curated somatic mutation records pooled across 44 studies (proportions of mutation calls, not per-patient prevalence); in a separate single-center Saudi cohort, only 3.7% of patients underwent BRCA testing, and 37.5% of this clinically selected, testing-referred subgroup carried a pathogenic variant, a figure that should not be read as general-population BRCA prevalence. Variants of uncertain significance exceeded 20% across several regional genomic studies. We summarize conserved driver events, such as recurrent TP53 and PIK3CA mutations, while highlighting regional features, including unique stop-gain and loss-of-function variants, a high copy-number burden, and early-onset disease linked to ancestral architecture. We also discuss emerging data on MENA-specific regulatory signatures, including immune-enriched and basal-myo transcriptomic clusters, CIMP-like methylation patterns, and non-coding RNA networks; these associations are numerically suggestive in available cohorts but have not reached statistical significance in existing studies and warrant validation in larger, dedicated MENA/Saudi cohorts before being considered established determinants of treatment response and resistance. Finally, we examine the clinical implications of this diversity for biomarker development, pharmacogenomics, and access to targeted therapies, and outline practical steps toward ancestry-aware precision oncology in the region.

BRCA↗
PubMed2000

Cyclin D1 in parathyroid disease.

Primary hyperparathyroidism (HPT), most commonly due to parathyroid adenoma, is a disorder characterized by excessive secretion of PTH. So far, abnormalities in two genes, cyclin D1 and MEN1, have been implicated in the development of parathyroid adenomas. Cyclin D1, now an established Oncogene involved in numerous human cancers, was first identified and recognized as an Oncogene in the study of parathyroid tumors. A subset of parathyroid adenomas contains a clonal rearrangement that places the PTH gene's regulatory sequences in proximity to the cyclin D1 Oncogene causing its overexpression, and 20-40% of parathyroid adenomas overexpress the cyclin D1 protein. Transgenic animal models have further confirmed the role of cyclin D1 as a driver of abnormal parathyroid cell proliferation. Future studies on the mechanism of cyclin D1's oncogenicity and its interactions with other parathyroid growth regulators will further our understanding of parathyroid cell biology and may prove useful clinically.

Cell Transformation, Neoplastic↗
PubMed2026

ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling.

Bladder cancer (BCa) mortality is mainly driven by metastatic dissemination and an immunosuppressive tumor microenvironment. Here, we identify ELN (tropoelastin), an extracellular matrix protein abundantly secreted by cancer-associated fibroblasts (CAFs), as a critical determinant of these processes and a marker of poor prognosis. ELN promotes epithelial-mesenchymal transition (EMT), facilitates lymphatic spread, and induces immune dysfunction characterized by macrophage polarization toward an M2 phenotype and T cell exhaustion. Mechanistically, ELN functions as a binding partner of TGF-β receptor 2 (TGFBR2), thereby triggering SMAD2/3-dependent TGF-β1 secretion and establishing a feed forward signaling loop. This ELN/TGFBR2/TGF-β1 axis amplifies metastatic capacity and immunosuppressive signaling, ultimately accelerating disease progression and diminishing responsiveness to immune checkpoint blockade. Functional studies in BCa organoids and murine models demonstrated that pharmacologic blockade of the ELN-TGFBR2 interaction effectively suppressed tumor metastasis and restored antitumor immunity. Collectively, our findings establish ELN as a CAF-derived driver of metastasis and immune evasion in BCa. Targeting the ELN-TGFBR2 interaction offers a promising therapeutic strategy to limit metastatic progression and enhance the efficacy of immunotherapy in this lethal disease.

Animals↗
PubMed1998

Lung cancer risk and workplace exposures in black men and women.

There are little data on workplace exposures and lung cancer risk in blacks. An ongoing case-control study of lung cancer that included 550 black men and women with lung cancer and 386 age-matched controls was examined by reported occupational exposures and job titles. In men, significant associations were observed with reported exposure to asbestos [odds ratio (OR), 1.8; 95% confidence intervals (CI) 1.03-3.1] and coal dust (OR, 2.8; 95% CI 1.1-7.0). Elevated but nonsignificant risks of 1.4 or more were detected for the following occupations: police/security guards, farmers/farm workers, laborers, and motor-vehicle drivers. In women, nonsignificant increased risks were found with reported exposure to paint (OR, 1.8) and gas fumes (OR, 4.9). Women employed as farmers/farm workers and building maintenance workers had elevated but nonsignificant risks.

Adult↗
PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗
PubMed2026

Metabolic-cell-death gene trio predicts survival and cuproptosis sensitivity in colorectal cancer.

BACKGROUND: Metabolic cell death (MCD) modulates colorectal cancer (CRC) progression, yet its prognostic value remains unexplored. We aimed to build an MCD-centred gene signature for outcome prediction and precision therapy. METHODS: Transcriptomes of 1,174 CRC patients were integrated. Weighted gene co-expression network analysis, differential expressions and least absolute shrinkage and selection operator (LASSO) + random survival forest were successively applied to derive a three-gene (CDKN2A/MPC1/AHCY) risk model. Functional, immune-infiltration, drug-sensitivity and genomic analyses were performed, followed by validation in fresh clinical specimens and cell lines. RESULTS: Integrative metabolic-death transcriptomics identified CDKN2A, MPC1 and AHCY as the hub drivers of CRC. Their three-gene signature robustly stratified patients into high- and low-risk subsets [3-year area under the curve (AUC) 0.83-0.85, P<0.001]. High-risk tumors were enriched for extracellular matrix (ECM)-receptor-interaction pathways, displayed abundant myeloid-derived suppressor cell (MDSC) infiltration and were more vulnerable to AZD8186, AZ960 and JAK inhibitors. Guided by these in-silico findings, we functionally confirmed that CDKN2A silencing markedly repressed proliferation, invasion and migration of SW480/HCT116 cells and potentiated cuproptosis via up-regulation of lipoylated DLAT/DLST and CTR1. CONCLUSIONS: We report the first MCD-derived prognostic platform for CRC that simultaneously predicts survival and therapeutic response. Targeting CDKN2A-enhanced cuproptosis represents a promising metabolic-precision strategy for high-risk patients.

Colorectal cancer (CRC)↗
PubMed2026

Exploring the Role of HSD17B2 in Colorectal Cancer Through Bioinformatic Analysis: Preliminary Insights for Prognostic Evaluation.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide. Although screening has reduced CRC in older adults, cases in younger individuals are rising, highlighting the need for early biomarkers. Emerging research highlights the role of estrogen metabolism in CRC progression, with enzymes such as hydroxysteroid (17-beta) dehydrogenase (HSD17B) being increasingly implicated. In this study, we performed a bioinformatics analysis using publicly available datasets, including The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort and two independent Gene Expression Omnibus (GEO) cohorts (GSE40967 and GSE41258), to investigate the role of HSD17B enzymes in CRC. Our results suggest that HSD17B2 is frequently downregulated in precancerous lesions and early-stage CRC, which may contribute to elevated estradiol levels and a tumor-promoting microenvironment. In advanced stages, higher HSD17B2 expression levels are associated with poorer survival outcomes in retrospective cohorts. Other HSD17B enzymes also exhibit significant expression changes, further complicating the hormonal landscape of CRC. In addition, estrone, traditionally considered a weaker estrogen, emerges as a potential driver of CRC progression. Our in-silico analyses indicate that HSD17B2 and HSD17B11 warrant further investigation as candidate biomarkers for distinguishing CRC from benign and precancerous conditions, with the combination showing strong discriminatory power in Receiver Operating Characteristic (ROC) analyses. Overall, these findings highlight the potential role of estrogen metabolism in CRC and suggest that HSD17B enzymes may hold value as candidate prognostic and diagnostic indicators, though their clinical utility remains hypothetical at this stage. Experimental and clinical validation is strictly required to confirm these in silico observations and to clarify their mechanisms in CRC.

Humans↗
PubMed2001

Molecular characterization of the T cell repertoire using immunoscope analysis and its possible implementation in clinical practice.

T lymphocytes play a central role in the pathogenesis of a large number of human conditions including autoimmunity and graft rejection. Although T cells are key players in mounting immune responses, the assessment of T cell repertoires has yet to find an important role in clinical decision making. In this review, we discuss the "immunoscope" technique and its potential diagnostic role in a variety of clinical scenarios. This is an RT-PCR based approach that subdivides a bulk T cell population (i. e. from blood, lymph, spleen, or tissue) into approximately 2800 groups based upon rearranged variable beta (Vbeta)/joining beta (Jbeta) gene segments and the resulting length of the T cell receptor's (TCR's) third complementarity determining region (CDR-3). This extensive subdivision, or focusing, allows clonal expansions to be directly observed. Such a fine-tuned analysis has revealed previously unappreciated aspects of the T cell repertoire. For instance, an antigen-specific immune response can be divided into both public and non-public components. The non-public repertoire contains the majority of the expanding T cells which are unique to the individual (private), or shared by only some (semi-private), while "public" T cells can be found responding to the antigenic determinant in every individual. Although they are often a minority of the response, the public T cell repertoire seems to play a more important role in defining, as well as driving, the overall immune phenotype in the animal. Immunoscope analysis has identified public and non-public responses in human pathologies, such as multiple sclerosis. The ability to characterize the driver T cells dictating the state of immunity/autoimmunity in individual patients will be an important step towards understanding autoimmunity and designing effective treatment for a variety of conditions including rheumatoid arthritis and multiple sclerosis. We review the current literature involving public and non-public repertoires and discuss the prospect that immunoscope analysis may play a central role in the study and perhaps the management of human autoimmune diseases, and cancer.

Animals↗
PubMed2005

Drivers of workplace discrimination against people with disabilities: the utility of Attribution Theory.

The purpose of this paper was to determine what drives workplace discrimination against people with disabilities. These findings are then compared to available literature on attribution theory, which concerns itself with public perceptions of the controllability and stability of various impairments. The sample included 35,763 allegations of discriminations filed by people with disabilities under the employment provisions of the Americans with Disabilities Act. Group A included impairments deemed by Corrigan et al. [1988] to be uncontrollable but stable: visual impairment (representing 13% of the total allegations in this study), cancer (12%), cardiovascular disease (19%), and spinal cord injuries (5%). The controllable but unstable impairments in group B included depression (38%), schizophrenia (2%), alcohol and other drug abuse (4%), and HIV/AIDS (7%). The Equal Employment Opportunity Commission had resolved all allegations in terms of merit Resolutions (a positive finding of discrimination) and Resolutions without merit. Allegations of workplace discrimination were found to center mainly on hiring, discharge, harassment, and reasonable accommodation issues. Perceived workplace discrimination (as measured by allegations filed with EEOC) does occur at higher levels in Group B, especially when serious issues involving discharge and disability harassment are involved. With the glaring exception of HIV/AIDS, however, actual discrimination (as measured by EEOC merit Resolutions) occurs at higher levels for Group A.

Adult↗
PubMed2026

Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5 destabilization in prostate cancer.

Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.

Male↗
PubMed2026

Genome-Wide In Vivo RNAi Screening Identifies HOXD4 as a Tumor Metastasis Suppressor in Colorectal Cancer.

Metastasis remains a major therapeutic challenge in colorectal cancer, highlighting an urgent need to elucidate its underlying molecular mechanisms. In this study, an in vivo screening system integrating genome-wide short hairpin RNA library and next-generation sequencing identifies six candidate metastasis suppressors, among which Homeobox D4 (HOXD4) shows the most pronounced effects. Clinicopathological analyses reveal significant HOXD4 downregulation in tumor tissues relative to adjacent normal tissues, with reduced expression strongly correlating with aggressive tumor features. Functional assays demonstrate that HOXD4 depletion enhances migration, invasion, and tumorsphere formation in HCT116 cells, while ectopic HOXD4 overexpression reverses these malignant phenotypes in SW620 cells. Mechanistically, HOXD4 suppresses epithelial-mesenchymal transition (EMT) by directly binding to the promoter of Forkhead box Q1 (FOXQ1), a key driver of EMT and stemness, and thereby transcriptionally repressing its expression. Immunohistochemistry confirms an inverse correlation between HOXD4 and FOXQ1 expression in clinical specimens. Rescue experiments substantiate that HOXD4 exerts its metastasis-suppressing functions via FOXQ1 regulation. Collectively, these findings not only establish an efficient platform for screening tumor metastasis suppressors, but also identify HOXD4 as a master transcriptional regulator of the FOXQ1-EMT axis, providing a promising target for metastasis interception.

Humans↗
PubMed2026

EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.

UNLABELLED: Diverse fusions of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) are oncogenic drivers in lung adenocarcinoma. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. In this study, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that variant 3 (V3) is more oncogenic than variant 1 (V1). By using multiplexed genome editing and quantifying the effects of 29 putative tumor-suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor-suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor-suppressor gene alterations on the biology of oncogenic fusion-driven cancers. SIGNIFICANCE: EML4-ALK-driven lung cancer is treated as a uniform disease despite the presence of distinct fusion variants in patients. Our findings show that EML4-ALK variants are functionally distinct, which may have implications for the treatment of this cancer type and highlights the need to consider differences among variants of other oncogenic fusions.

Animals↗
PubMed1995

Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management.

Eleven patients with cancer pain in a palliative care and chronic pain service required cessation of morphine due to unacceptable opioid side effects. In this retrospective study fentanyl was evaluated as a second-line subcutaneously infused opioid. Starting doses ranged from 100 to 1000 micrograms/24 h, and the duration of fentanyl infusion was 3-70 days. The clinically derived mean relative potency of fentanyl to morphine infusions was 68:1 (SD +/- 23; range: 15-100), and we now recommend cautious dose conversion at an approximate equivalence of 150-200 micrograms fentanyl for 10 mg morphine in non-opioid naive chronic cancer pain patients. All patients demonstrated an improvement in the adverse effect(s) for which the change in opioid was undertaken. Adequate pain relief was achieved in all but 1 patient with mixed nociceptive and neuropathic pelvic pain for whom an epidural infusion of a local anaesthetic/opioid mixture was required. Fentanyl was changed to the more potent synthetic opioid sufentanil in 2 patients for whom the fentanyl dose necessitated too large a volume for the portable syringe driver in use. The clinically derived sufentanil to fentanyl relative potencies were 24:1 and 16:1, respectively. This achieved good analgesia and maintained the favourable side-effect profile seen with fentanyl. Subcutaneous infusion appears to be a safe and viable route of fentanyl delivery, and provided effective analgesia with a low incidence of adverse effects in this small selected group of patients who were intolerant of subcutaneous morphine. We suggest a trial of subcutaneous fentanyl for selected patients who have intractable adverse effects on morphine, and it is now the second-line infusable opioid in our service. Further prospective evaluation of the role of these two synthetic mu opioid agonists in palliative care practice is warranted, as part of an evolving picture of variation in opioid side-effect profile seen with different drugs within the class.

Adult↗
PubMed1999

The micronucleus assay in exfoliated buccal cells: application to occupational exposure to polycyclic aromatic hydrocarbons.

Many polycyclic aromatic hydrocarbons (PAHs) have been identified as cancer-inducing chemicals for animals and/or humans. Also, there is sufficient evidence that exposures in the occupational settings are carcinogenic or probably carcinogenic to human. Engine exhaust and used engine oils are major PAH sources in engine repair workshops and traffic. Analysis of micronucleus (MN) in exfoliated buccal cells is a sensitive method for monitoring genetic damage in human populations. In our study, we used three different occupational groups (Group 1; engine repair workers, Group 2; taxi drivers, Group 3; traffic police) and two controls (Control I for Group 1 and Control II for Group 2 and Group 3) for the exposed groups. We analysed MN frequencies in exfoliated buccal cells and compared the exposed groups (Group 1; n=34, Group 2; n=17, Group 3; n=15) and subjects not occupationally exposed to PAH (Control I; n=28, Control II; n=20). The mean (+/-S.D.) MN (%) frequencies in exfoliated buccal cells from Group 1 and Control I were 0.07+/-0.05 and 0. 05+/-0.04, respectively (p>0.05; Table 2). The mean (+/-S.D.) MN (%) frequencies in exfoliated buccal cells from Group 2, 3 and Control II were 0.12+/-0.05, 0.10+/-0.05 and 0.03+/-0.03, respectively (p<0. 0001, p<0.05; Table 2) Smokers and nonsmokers do not differ with respect to the incidence of MN in all groups.

Adolescent↗