| 1. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 2. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 3. |
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| 4. |
- Lopez, F, et al.
(författare)
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Neck Surgery for Non-Well Differentiated Thyroid Malignancies: Variations in Strategy According to Histopathology
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Lymph node metastases in non-well differentiated thyroid cancer (non-WDTC) are common, both in the central compartment (levels VI and VII) and in the lateral neck (Levels II to V). Nodal metastases negatively affect prognosis and should be treated to maximize locoregional control while minimizing morbidity. In non-WDTC, the rate of nodal involvement is variable and depends on the histology of the tumor. For medullary thyroid carcinomas, poorly differentiated thyroid carcinomas, and anaplastic thyroid carcinomas, the high frequency of lymph node metastases makes central compartment dissection generally necessary. In mucoepidermoid carcinomas, malignant peripheral nerve sheath tumors, sarcomas, and malignant thyroid teratomas or thyroblastomas, central compartment dissection is less often necessary, as clinical lymphnode involvement is less common. We aim to summarize the medical literature and the opinions of several experts from different parts of the world on the current philosophy for managing the neck in less common types of thyroid cancer.
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| 5. |
- Lopez, F, et al.
(författare)
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Update on olfactory neuroblastoma
- 2024
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Ingår i: Virchows Archiv : an international journal of pathology. - 1432-2307. ; 484:34, s. 567-585
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Tidskriftsartikel (refereegranskat)
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| 6. |
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| 7. |
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| 8. |
- Vander Poorten, V., et al.
(författare)
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Polymorphous adenocarcinoma of the salivary glands: reappraisal and update
- 2018
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Ingår i: European Archives of Oto-Rhino-Laryngology. - : Springer Science and Business Media LLC. - 0937-4477 .- 1434-4726. ; 275:7, s. 1681-1695
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Tidskriftsartikel (refereegranskat)abstract
- Although relatively rare, polymorphous adenocarcinoma (PAC) is likely the second most common malignancy of the minor salivary glands (MiSG). The diagnosis is mainly based on an incisional biopsy. The optimal treatment comprises wide surgical excision, often with adjuvant radiotherapy. In general, PAC has a good prognosis. Previously, PAC was referred to as polymorphous low-grade adenocarcinoma (PLGA), but the new WHO classification of salivary gland tumours has also included under the PAC subheading, the so-called cribriform adenocarcinoma of minor salivary glands (CAMSG). This approach raised controversy, predominantly because of possible differences in clinical behaviour. For example, PLGA (PAC, classical variant) only rarely metastasizes, whereas CAMSG often shows metastases to the neck lymph nodes. Given the controversy, this review reappraises the definition, epidemiology, clinical presentation, diagnostic work-up, genetics, treatment modalities, and prognosis of PAC of the salivary glands with a particular focus on contrasting differences with CAMSG.
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| 13. |
- Gregoire, V, et al.
(författare)
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Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines
- 2018
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Ingår i: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. - : Elsevier BV. - 1879-0887. ; 126:1, s. 3-24
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Tidskriftsartikel (refereegranskat)
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| 14. |
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| 15. |
- Rodrigo, J. P., et al.
(författare)
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Neutrophil to Lymphocyte Ratio in Oropharyngeal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
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Forskningsöversikt (refereegranskat)abstract
- Simple Summary Neutrophil-to-lymphocyte ratio (NLR) in peripheral blood samples has been associated with prognosis in several cancers, including head and neck cancer, but in oropharyngeal carcinomas its prognostic value, especially in relation to human papillomavirus (HPV) infection, has been little studied. This meta-analysis, including studies on the prognostic value of NLR in oropharyngeal carcinoma, shows that an elevated pretreatment NLR is associated with a worse prognosis in oropharyngeal cancer, regardless of the type of treatment performed, but this prognostic value appears to be specific to HPV-positive oropharyngeal carcinomas. NLR could be used as an affordable prognostic marker in this type of cancer. Neutrophil-to-lymphocyte ratio (NLR) has been associated with survival in various cancers, including head and neck cancer. However, there is limited information on its role in oropharyngeal squamous cell carcinomas (OPSCC) according to HPV status. This prompted the present meta-analysis. Studies were selected when the prognostic value of NLR prior to treatment was evaluated in OPSCC patients, the cutoff value of NLR was available, and the prognostic value of NLR was evaluated by time-to-event survival analysis. A total of 14 out of 492 articles, including 7647 patients, were analyzed. The results showed a worse prognosis for the patients with a high NLR: The combined hazard ratios (HR) for overall survival (OS) in patients with an elevated NLR was 1.56 (95% confidence interval (CI) 1.21-2.02; p = 0.0006), for disease-free survival was 1.52 (95% CI 1.34-1.73; p < 0.00001), and for recurrence-free survival was 1.86 (95% CI 1.50-2.30; p < 0.00001). This worse prognosis of high NLR was exclusive of HPV-positive patients: HR for OS in the HPV-positive subgroup was 4.05 (95% CI 1.90-8.62 (p = 0.0003), and in the HPV-negative subgroup 0.92 (95% CI 0.47-1.80; p = 0.82). The prognosis of NLR was not influenced by treatment: The HR for OS for patients treated with radiotherapy/chemoradiotherapy (RT/CRT) was 1.48 (95% CI 1.09-2.01; p = 0.01), and for patients treated with surgery (+/- RT/CRT) was 1.72 (95% CI 1.08-2.72; p = 0.02). In conclusion, an elevated NLR relates to worse outcomes in patients with HPV-positive OPSCC.
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| 16. |
- Ronen, O, et al.
(författare)
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Standardization for oncologic head and neck surgery
- 2021
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Ingår i: European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. - : Springer Science and Business Media LLC. - 1434-4726. ; 278:12, s. 4663-4669
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Tidskriftsartikel (refereegranskat)
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| 22. |
- Cavalheiro, BG, et al.
(författare)
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Management of Recurrent Well-Differentiated Thyroid Carcinoma in the Neck: A Comprehensive Review
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Surgery has been historically the preferred primary treatment for patients with well-differentiated thyroid carcinoma and for selected locoregional recurrences. Adjuvant therapy with radioactive iodine is typically recommended for patients with an intermediate to high risk of recurrence. Despite these treatments, locally advanced disease and locoregional relapses are not infrequent. These patients have a prolonged overall survival that may result in long periods of active disease and the possibility of requiring subsequent treatments. Recently, many new options have emerged as salvage therapies. This review offers a comprehensive discussion and considerations regarding surgery, active surveillance, radioactive iodine therapy, ultrasonography-guided percutaneous ablation, external beam radiotherapy, and systemic therapy for well-differentiated thyroid cancer based on relevant publications and current reference guidelines. We feel that the surgical member of the thyroid cancer management team is empowered by being aware and facile with all management options.
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| 33. |
- Kreutzberger, AJB, et al.
(författare)
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SARS-CoV-2 requires acidic pH to infect cells
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:38, s. e2209514119-
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry starts with membrane attachment and ends with spike (S) protein–catalyzed membrane fusion depending on two cleavage steps, namely, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time three-dimensional single-virion tracking, we show that fusion and genome penetration require virion exposure to an acidic milieu of pH 6.2 to 6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2-overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2-expressing cells in the acidic milieu of the nasal cavity.
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| 34. |
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| 35. |
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| 36. |
- Lopez, F, et al.
(författare)
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Qualitative and Quantitative Diagnosis in Head and Neck Cancer
- 2021
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Ingår i: Diagnostics (Basel, Switzerland). - : MDPI AG. - 2075-4418. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis is the art of determining the nature of a disease, and an accurate diagnosis is the true cornerstone on which rational treatment should be built. Within the workflow in the management of head and neck tumours, there are different types of diagnosis. The purpose of this work is to point out the differences and the aims of the different types of diagnoses and to highlight their importance in the management of patients with head and neck tumours. Qualitative diagnosis is performed by a pathologist and is essential in determining the management and can provide guidance on prognosis. The evolution of immunohistochemistry and molecular biology techniques has made it possible to obtain more precise diagnoses and to identify prognostic markers and precision factors. Quantitative diagnosis is made by the radiologist and consists of identifying a mass lesion and the estimation of the tumour volume and extent using imaging techniques, such as CT, MRI, and PET. The distinction between the two types of diagnosis is clear, as the methodology is different. The accurate establishment of both diagnoses plays an essential role in treatment planning. Getting the right diagnosis is a key aspect of health care, and it provides an explanation of a patient’s health problem and informs subsequent decision. Deep learning and radiomics approaches hold promise for improving diagnosis.
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| 42. |
- Pekkinen, M., et al.
(författare)
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Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2
- 2019
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Ingår i: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 4:7
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated 6 families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.IIe62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.IIe62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasial Several subjects had experienced peripheral facial nerve palsy or other neurological manifestations. Bone biopsies showed markedly altered bone material characteristics, including defective bone mineralization. Osteoclast formation and function in vitro was normal. While the p.Arg50* mutation yielded a catalytically inactive enzyme, p.IIe62Ser and p.Met64Arg each enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. SGMS2 pathogenic variants underlie a spectrum of skeletal conditions, ranging from isolated osteoporosis to complex skeletal dysplasia, suggesting a critical role for plasma membrane-bound sphingomyelin metabolism in skeletal homeostasis.
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| 43. |
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| 44. |
- Ronen, O, et al.
(författare)
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Case for staged thyroidectomy
- 2020
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Ingår i: Head & neck. - : Wiley. - 1097-0347 .- 1043-3074. ; 42:10, s. 3061-3071
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Tidskriftsartikel (refereegranskat)
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| 45. |
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| 48. |
- Sanabria, A, et al.
(författare)
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Incidence of Occult Lymph Node Metastasis in Primary Larynx Squamous Cell Carcinoma, by Subsite, T Classification and Neck Level: A Systematic Review
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Larynx cancer is a common site for tumors of the upper aerodigestive tract. In cases with a clinically negative neck, the indications for an elective neck treatment are still debated. The objective is to define the prevalence of occult metastasis based on the subsite of the primary tumor, T classification and neck node levels involved. Methods: All studies included provided the rate of occult metastases in cN0 larynx squamous cell carcinoma patients. The main outcome was the incidence of occult metastasis. The pooled incidence was calculated with random effects analysis. Results: 36 studies with 3803 patients fulfilled the criteria. The incidence of lymph node metastases for supraglottic and glottic tumors was 19.9% (95% CI 16.4–23.4) and 8.0% (95% CI 2.7–13.3), respectively. The incidence of occult metastasis for level I, level IV and level V was 2.4% (95% CI 0–6.1%), 2.0% (95% CI 0.9–3.1) and 0.4% (95% CI 0–1.0%), respectively. For all tumors, the incidence for sublevel IIB was 0.5% (95% CI 0–1.3). Conclusions: The incidence of occult lymph node metastasis is higher in supraglottic and T3–4 tumors. Level I and V and sublevel IIB should not be routinely included in the elective neck treatment of cN0 laryngeal cancer and, in addition, level IV should not be routinely included in cases of supraglottic tumors.
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| 49. |
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| 50. |
- Tuomainen, K, et al.
(författare)
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High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 14755-
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Tidskriftsartikel (refereegranskat)abstract
- Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. Here, we performed a high-throughput compound screen to identify a synergistic interaction between ionizing radiation and 396 anticancer compounds. The assay was run using five human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) cell lines cultured on the human tumor-derived matrix Myogel. Our screen identified several compounds with strong synergistic and antagonistic effects, which we further investigated using multiple irradiation doses. Navitoclax, which emerged as the most promising radiosensitizer, exhibited synergy with irradiation regardless of the p53 mutation status in all 13 HNSCC cell lines. We performed a live cell apoptosis assay for two representative HNSCC cell lines to examine the effects of navitoclax and irradiation. As a single agent, navitoclax reduced proliferation and induced apoptosis in a dose-dependent manner, whereas the navitoclax–irradiation combination arrested cell cycle progression and resulted in substantially elevated apoptosis. Overall, we demonstrated that combining navitoclax with irradiation resulted in synergistic in vitro antitumor effects in HNSCC cell lines, possibly indicating the therapeutic potential for HNSCC patients.
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