Comparative analysis of 10X Chromium vs. BD Rhapsody whole transcriptome single-cell sequencing technologies in complex human tissues.

The development of single-cell omics tools has enabled scientists to study the tumor microenvironment (TME) in unprecedented detail. However, each of the different techniques may have its unique strengths and limitations. Here we directly compared two commercially available high-throughput single-cell RNA sequencing (scRNA-seq) technologies - droplet-based 10X Chromium vs. microwell-based BD Rhapsody - using paired samples from patients with localized prostate cancer (PCa) undergoing a radical prostatectomy. Although high technical consistency was observed in unraveling the whole transcriptome, the relative abundance of cell populations differed. Cells with low mRNA content such as T cells were underrepresented in the droplet-based system, at least partly due to lower RNA capture rates. In contrast, microwell-based scRNA-seq recovered less cells of epithelial origin. Moreover, we discovered platform-dependent variabilities in mRNA quantification and cell-type marker annotation. Overall, our study provides important information for selection of the appropriate scRNA-seq platform and for the interpretation of published results.

Preclinical Efficacy of a PSMA-Targeted Actinium-225 Conjugate (225Ac-Macropa-Pelgifatamab): A Targeted Alpha Therapy for Prostate Cancer.

PURPOSE: Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs. EXPERIMENTAL DESIGN: The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide. RESULTS: Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models. CONCLUSIONS: These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306).

Machine Learning to Identify Critical Biomarker Profiles in New SARS-CoV-2 Variants.

The global dissemination of SARS-CoV-2 resulted in the emergence of several variants, including Alpha, Alpha + E484K, Beta, and Omicron. Our research integrated the study of eukaryotic translation factors and fundamental components in general protein synthesis with the analysis of SARS-CoV-2 variants and vaccination status. Utilizing statistical methods, we successfully differentiated between variants in infected individuals and, to a lesser extent, between vaccinated and non-vaccinated infected individuals, relying on the expression profiles of translation factors. Additionally, our investigation identified common causal relationships among the translation factors, shedding light on the interplay between SARS-CoV-2 variants and the host's translation machinery.

[Digital pathology in Austria]. / Digitale Pathologie in Österreich.

The situation regarding digital pathology in Austria is manageable compared to other countries. Active Austrian examples are the consortium EMPAIA, the private-public partnership Bigpicture, the Austrian Society for Clinical Pathology and Molecular Pathology (OEGPath), the company TissueGnostics, and the Austrian Platform for Personalized Medicine (OEPPM).

Endometriosis-Associated Ovarian Carcinomas: How PI3K/AKT/mTOR Pathway Affects Their Pathogenesis.

Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term "endometriosis-associated ovarian cancer" (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is known to be aberrantly activated both in endometriosis and EAOC; however, its role in the progression of endometriosis to ovarian cancer remains unclear. In fact, cancer-associated alterations in the mTOR pathway may be found in normal uterine epithelium, likely acting as a first step towards ovarian cancer, through the intermediary stage of endometriosis. This review aims to summarize the current knowledge regarding mTOR signaling dysregulation in the uterine endometrium, endometriosis, and EAOC while focusing on the interconnections between the PI3K/AKT/mTOR pathway and other signaling molecules that give rise to synergistic molecular mechanisms triggering ovarian cancer development in the presence of endometriosis.

Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-30% of breast cancers but has low expression in normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive breast cancer typically metastasizes to bone, resulting in incurable disease and significant morbidity and mortality. Therefore, new strategies for HER2-targeting therapy are needed. Here, we present the preclinical in vitro and in vivo characterization of the HER2-targeted thorium-227 conjugate (HER2-TTC) TAT in various HER2-positive cancer models. In vitro, HER2-TTC showed potent cytotoxicity in various HER2-expressing cancer cell lines and increased DNA double strand break formation and the induction of cell cycle arrest in BT-474 cells. In vivo, HER2-TTC demonstrated dose-dependent antitumor efficacy in subcutaneous xenograft models. Notably, HER2-TTC also inhibited intratibial tumor growth and tumor-induced abnormal bone formation in an intratibial BT-474 mouse model that mimics breast cancer metastasized to bone. Furthermore, a match in HER2 expression levels between primary breast tumor and matched bone metastases samples from breast cancer patients was observed. These results demonstrate proof-of-concept for TAT in the treatment of patients with HER2-positive breast cancer, including cases where the tumor has metastasized to bone.

A Targeted Thorium-227 Conjugate Demonstrates Efficacy in Preclinical Models of Acquired Drug Resistance and Combination Potential with Chemotherapeutics and Antiangiogenic Therapies.

Targeted alpha therapies (TAT) are an innovative class of therapies for cancer treatment. The unique mode-of-action of TATs is the induction of deleterious DNA double-strand breaks. Difficult-to-treat cancers, such as gynecologic cancers upregulating the chemoresistance P-glycoprotein (p-gp) and overexpressing the membrane protein mesothelin (MSLN), are promising targets for TATs. Here, based on the previous encouraging findings with monotherapy, we investigated the efficacy of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) both as monotherapy and in combination with chemotherapies and antiangiogenic compounds in ovarian and cervical cancer models expressing p-gp. MSLN-TTC monotherapy showed equal cytotoxicity in vitro in p-gp-positive and -negative cancer cells, while chemotherapeutics dramatically lost activity on p-gp-positive cancer cells. In vivo, MSLN-TTC exhibited dose-dependent tumor growth inhibition with treatment/control ratios of 0.03-0.44 in various xenograft models irrespective of p-gp expression status. Furthermore, MSLN-TTC was more efficacious in p-gp-expressing tumors than chemotherapeutics. In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (Doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp-expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies.

Expression of Eukaryotic Translation Initiation Factors in the Urothelial Carcinoma of the Bladder.

BACKGROUND/AIM: Urothelial carcinoma (UC) of the urinary bladder is the second most common tumor in the field of urology and is characterized by a relatively aggressive growth behavior. New therapeutic approaches are required to improve the prognosis of affected patients. We hypothesized a link between dysregulation of eIFs and the development of UC. Therefore, in the present work, we investigated the expression behavior of eIF1, eIF1AY, eIF1AX, eIF2α, eIF3a, eIF3b, eIF4B, eIF4E, eIF4G, eIF5A, eIF5B, and eIF6 in UC compared with that in urothelial tissue. MATERIALS AND METHODS: Paraffin-embedded tumor tissue samples from 107 patients suffering from UC were examined. Seventy-six patients contained adjacent urothelial tissue. Three tumor tissue cylinders (tumor collective) and two urothelial tissue cylinders (control collective) were collected per patient and embedded in tissue microarray (TMA) blocks. Immunohistochemical staining of the TMA sections was then performed. The staining results were assessed semi-quantitatively. Staining intensities and immunoreactive scores (IRS) of both collectives were compared. In each case, a distinction was made between cytoplasmic and nuclear staining. RESULTS: Significant up-regulation of eIF1AY, eIF2α, eIF3a, eIF3b, eIF4B, eIF4G, eIF5B, and eIF6 was found in the cytoplasm of UC. In contrast, eIF1 and eIF5A were significantly down-regulated in the cytoplasm of UC. eIF5A and eIF6 were significantly down-regulated in the nuclei of UC. CONCLUSION: Dysregulation of eIFs in the urothelium of the urinary bladder is linked to carcinogenesis at this site.

Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model.

Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. In vitro experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced in vivo antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.

Minimally Invasive Cytopathology and Accurate Diagnosis: Technical Procedures and Ancillary Techniques.

In recent years, the demand for cytopathological accurate diagnoses has increased as expanding minimally invasive procedures obtain materials from patients with advanced cancer for diagnostic, prognostic, and predictive purposes. However, inadequate knowledge of cytopathological technical procedures and ancillary techniques by clinicians remains the most common reason for the limited availability of cytopathology. The objectives of this review were to understand the technical procedures, ancillary techniques, and application and effectiveness of various types of tests in cytopathology. Each of the many ancillary technologies described in the literature has specific advantages and limitations and laboratories select one or more methods depending on their infrastructure and expertise to achieve the goal from initial screening of the disease to the final diagnosis of the cytopathology. This paper systematically reviews the development of cytopathology, summarizes the existing problems in cytopathology and the new progress of auxiliary examination, to provide a theoretical basis for the advanced development of cytopathological diagnostic technologies and to consolidate the minimally invasive and accurate diagnosis of cytopathologies for clinicians. Cytopathology offers many advantages over other clinical examinations, particularly for minimally invasive and accurate diagnosis.

LncRNA TUG1 promotes the migration and invasion in type I endometrial carcinoma cells by regulating E-N cadherin switch.

OBJECTIVE: Accumulating evidence has demonstrated that lncRNA Taurine-upregulated gene 1 (TUG1) plays an important role in regulation of cell morphology, migration, proliferation and apoptosis. Our aim was to evaluate the oncogenic role of TUG1 in type I Endometrial Carcinoma (EC) and explore the precise mechanism of TUG1 involved in tumor progression. MATERIALS AND METHODS: The GSE17025 data set was used to analyze the correlation of TUG1 expression with type I EC patients' prognosis. Furthermore, TUG1 expression profiles were measured by qRT-PCR from carcinoma tissues and adjacent nonneoplastic tissues (NNT) of 105 type I EC patients. The regulation of epithelial-mesenchymal transition (EMT) related molecules, p-AKT and AKT by TUG1 knockdown was investigated using Western blot analysis; meanwhile, the oncogenic roles of TUG1 were evaluated using cell viability and transwell migration/invasion assay in Hec-1-A and Ishikawa cell lines. RESULTS: Firstly, we observed a significant association between higher TUG1 expression and lower survival rate in type I EC patients using the GSE17025 data set. A significant elevation of TUG1 levels was confirmed in type I EC tissues compared with NNT in the 105 type I EC patients, and high expression of TUG1 was associated with lymph vascular space invasion (LVSI) and lymph node metastasis (LNM). Subsequently, TUG1 knockdown could remarkably inhibit the Hec-1-A and Ishikawa cell invasion and migration in the functional experiment. Furthermore, our results showed that the protein levels of E-cadherin increased and N-cadherin decreased significantly, while ß-catenin and Vimentin were not significantly altered upon TUG1 silencing in both Hec-1-A and Ishikawa cells. Finally, we found the p-AKT and AKT protein levels, and the rate of p-AKT/t-AKT has a tendency to be down-regulate in Hec-1-A cells, while the AKT pathway was not change significantly in Ishikawa cells after TUG1 knockdown. CONCLUSION: Collectively, our data reveal that TUG1 might be regarded as an oncogenic molecule that promotes type I EC cells metastasis leading to tumor progression, at least partially, by regulating E-N cadherin switch and the AKT pathway.

MIO: microRNA target analysis system for immuno-oncology.

SUMMARY: MicroRNAs have been shown to be able to modulate the tumor microenvironment and the immune response and hence could be interesting biomarkers and therapeutic targets in immuno-oncology; however, dedicated analysis tools are missing. Here, we present a user-friendly web platform MIO and a Python toolkit miopy integrating various methods for visualization and analysis of provided or custom bulk microRNA and gene expression data. We include regularized regression and survival analysis and provide information of 40 microRNA target prediction tools as well as a collection of curated immune related gene and microRNA signatures and processed TCGA data including estimations of infiltrated immune cells and the immunophenoscore. The integration of several machine learning methods enables the selection of prognostic and predictive microRNAs and gene interaction network biomarkers. AVAILABILITY AND IMPLEMENTATION: https://mio.icbi.at, https://github.com/icbi-lab/mio and https://github.com/icbi-lab/miopy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Initiation and elongation factor co-expression correlates with recurrence and survival in epithelial ovarian cancer.

High grade epithelial ovarian cancer (EOC) represents a diagnostic and therapeutic challenge due to its aggressive features and short recurrence free survival (RFS) after primary treatment. Novel targets to inform our understanding of the EOC carcinogenesis in the translational machinery can provide us with independent prognostic markers and provide drugable targets. We have identified candidate eukaryotic initiation factors (eIF) and eukaryotic elongation factors (eEF) in the translational machinery for differential expression in EOC through in-silico analysis. We present the analysis of 150 ovarian tissue microarray (TMA) samples on the expression of the translational markers eIF2α, eIF2G, eIF5 (eIF5A and eIF5B), eIF6 and eEF1A1. All translational markers were differentially expressed among non-neoplastic ovarian samples and tumour samples (borderline tumours and EOC). In EOC, expression of eIF5A was found to be significantly correlated with recurrence free survival (RFS) and expression of eIF2G and eEF1A1 with overall survival (OS). Expression correlation among factor subunits showed that the correlation of eEF1A1, eIF2G, EIF2α and eIF5A were significantly interconnected. eIF5A was also correlated with eIF5B and eIF6. Our study demonstrates that EOCs have different translational profile compared to benign ovarian tissue and that eIF5A is a central dysregulated factor of the translation machinery.

Unlaid Eggs: Ovarian Damage after Low-Dose Radiation.

The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.

The Role of mTOR and eIF Signaling in Benign Endometrial Diseases.

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.

The Translational Bridge between Inflammation and Hepatocarcinogenesis.

Viral infections or persistent alcohol or drug abuse, together with intrinsic factors, lead to hepatitis, which often ends in the development of liver cirrhosis or hepatocellular carcinoma (HCC). With this review, we describe inflammatory liver diseases, such as acute liver failure, virus-induced hepatitis, alcoholic- and non-alcoholic steatohepatitis, and autoimmune hepatitis, and highlight their driving mechanisms. These include external factors such as alcohol misuse, viral infection and supernutrition, as well as intrinsic parameters such as genetic disposition and failure, in immune tolerance. Additionally, we describe what is known about the translational machinery within all these diseases. Distinct eukaryotic translation initiation factors (eIFs) with specific functional roles and aberrant expression in HCC are reported. Many alterations to the translational machinery are already triggered in the precancerous lesions described in this review, highlighting mTOR pathway proteins and eIFs to emphasize their putative clinical relevance. Here, we identified a lack of knowledge regarding the roles of single eIF proteins. A closer investigation will help to understand and treat HCC as well as the antecedent diseases.

Nrf2 in the Field of Dentistry with Special Attention to NLRP3.

The aim of this review article was to summarize the functional implications of the nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2 (Nrf2), with special attention to the NACHT (nucleotide-binding oligomerization), LRR (leucine-rich repeat), and PYD (pyrin domain) domains-containing protein 3 (NLRP3) inflammasome in the field of dentistry. NLRP3 plays a crucial role in the progression of inflammatory and adaptive immune responses throughout the body. It is already known that this inflammasome is a key regulator of several systemic diseases. The initiation and activation of NLRP3 starts with the oral microbiome and its association with the pathogenesis and progression of several oral diseases, including periodontitis, periapical periodontitis, and oral squamous cell carcinoma (OSCC). The possible role of the inflammasome in oral disease conditions may involve the aberrant regulation of various response mechanisms, not only in the mouth but in the whole body. Understanding the cellular and molecular biology of the NLRP3 inflammasome and its relationship to Nrf2 is necessary for the rationale when suggesting it as a potential therapeutic target for treatment and prevention of oral inflammatory and immunological disorders. In this review, we highlighted the current knowledge about NLRP3, its likely role in the pathogenesis of various inflammatory oral processes, and its crosstalk with Nrf2, which might offer future possibilities for disease prevention and targeted therapy in the field of dentistry and oral health.

Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine.

BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.

Targeted thorium-227 conjugates as treatment options in oncology.

Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer therapy, including high linear energy transfer (LET), penetration range of 2-10 cell layers, induction of complex double-stranded DNA breaks, and immune-stimulatory effects. Several alpha radionuclides, including radium-223 (223Ra), actinium-225 (225Ac), and thorium-227 (227Th), have been investigated. Conjugation of tumor targeting modalities, such as antibodies and small molecules, with a chelator moiety and subsequent radiolabeling with α-emitters enables specific delivery of cytotoxic payloads to different tumor types. 223Ra dichloride, approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-metastatic disease and no visceral metastasis, is the only approved and commercialized alpha therapy. However, 223Ra dichloride cannot currently be complexed to targeting moieties. In contrast to 223Ra, 227Th may be readily chelated, which allows radiolabeling of tumor targeting moieties to produce targeted thorium conjugates (TTCs), facilitating delivery to a broad range of tumors. TTCs have shown promise in pre-clinical studies across a range of tumor-cell expressing antigens. A clinical study in hematological malignancy targeting CD22 has demonstrated early signs of activity. Furthermore, pre-clinical studies show additive or synergistic effects when TTCs are combined with established anti-cancer therapies, for example androgen receptor inhibitors (ARI), DNA damage response inhibitors such as poly (ADP)-ribose polymerase inhibitors or ataxia telangiectasia and Rad3-related kinase inhibitors, as well as immune checkpoint inhibitors.

DNA repair inhibitors sensitize cells differently to high and low LET radiation.

The aim of this study was to investigate effects of high LET α-radiation in combination with inhibitors of DDR (DNA-PK and ATM) and to compare the effect with the radiosensitizing effect of low LET X-ray radiation. The various cell lines were irradiated with α-radiation and with X-ray. Clonogenic survival, the formation of micronuclei and cell cycle distribution were studied after combining of radiation with DDR inhibitors. The inhibitors sensitized different cancer cell lines to radiation. DNA-PKi affected survival rates in combination with α-radiation in selected cell lines. The sensitization enhancement ratios were in the range of 1.6-1.85 in cancer cells. ATMi sensitized H460 cells and significantly increased the micronucleus frequency for both radiation qualities. ATMi in combination with α-radiation reduced survival of HEK293. A significantly elicited cell cycle arrest in G2/M phase after co-treatment of ATMi with α-radiation and X-ray. The most prominent treatment effect was observed in the HEK293 by combining α-radiation and inhibitions. ATMi preferentially sensitized cancer cells and normal HEK293 cells to α-radiation. DNA-PKi and ATMi can sensitize cancer cells to X-ray, but the effectiveness was dependent on cancer cells itself. α-radiation reduced proliferation in primary fibroblast without G2/M arrest.