lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer.

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real-time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull-down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain- and loss-of-function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.

Genetically Proxied Sarcopenia-Related Muscle Traits and Depression: Evidence from the FinnGen Cohort.

BACKGROUND: Sarcopenia and depression are common and often coexist in the elderly. This study aims to determine the impact of sarcopenia-related muscle traits on depression. METHODS: A two-sample Mendelian randomization (MR) study was performed on the summary-level data from the FinnGen cohort to estimate the causal association of appendicular lean mass (ALM), walking pace, or low hand grip strength with depression. Additionally, multivariable MR (MVMR) was performed to assess the dependence of each muscle trait in the causality and adjust the effect of body mass index (BMI). Supplementary backward MR analyses were performed to estimate the effect of depression on sarcopenia-related muscle traits. RESULTS: Univariable MR analyses demonstrated that there were causal associations of ALM (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.88-0.99), walking pace (OR: 0.53; 95% CI: 0.32-0.88), and low hand grip strength (OR: 1.20; 95% CI: 1.05-1.38) with depression. MVMR analyses showed that ALM was the only trait that had a significant causal relationship with depression (OR: 0.91; 95% CI: 0.85-0.98) after accounting for the other two muscle traits. Moreover, the independent association of ALM with depression remained (OR: 0.92; 95% CI: 0.85-0.99) after being adjusted by BMI. The backward MR analyses showed no causal associations of depression with any sarcopenia-related muscle traits. CONCLUSION: Low muscle mass independently increases the risk of depression. This study determined the muscle-related risk factors of depression, which may help establish the causality between sarcopenia and depression and provide evidence-based recommendations for improving mental health in the elderly.

Effective doses of midazolam oral solution for the prevention of preoperative anxiety in paediatric patients.

BACKGROUND: More than 60% children exhibit anxiety before undergoing an anesthetic-surgical procedure, particularly among pre-school paediatric patients. Oral midazolam can provide procedural sedation for children prior to anesthesia. However, extemporaneous solutions of midazolam are usually prepared from injectable drug solutions, leading to inconsistent efficacy due to variable preparation methods. Xiaoerjing® is the first commercially available oral formulation of midazolam for procedural sedation in children in China. Despite the recommended dosage range of 0.25-0.5 mg/kg, its effective dose is still largely unknown. AIM: To determine the 95% effective dose (ED95) of midazolam oral solution (Xiaoerjing®) for alleviating preoperative anxiety in children prior to mask induction of general anesthesia. DESIGN: The study included 61 children between the ages of 1 and 6 years undergoing elective surgery under general anesthesia. The first patient received a single dose of 0.5 mg/kg midazolam oral solution, which was adjusted for subsequent patients using the biased coin design method based on their response to the previous dose. Doses were increased or decreased at the rate of 0.1 mg/kg. An effective response was defined as having a modified Ramsay sedation score ≥3a, separation anxiety score ≤2, and mask acceptance score ≤2 during inhalational anesthesia induction. RESULTS: Fifty-six children were included in the final analysis. Of those, sedation was successful in 50 patients, with a median separation time of 15 (IQR: 25) min. Midazolam oral solution has an ED95 of 0.8254 mg/kg (95% CI: 0.6915-0.8700 mg/kg) for relieving preoperative anxiety in children. No adverse events occurred following drug administration. CONCLUSION: Midazolam oral solution is a safe and effective medication for relieving preoperative anxiety in children. The ED95 of a single oral dose of midazolam oral solution is 0.8254 mg/kg (95% CI: 0.6915-0.8700 mg/kg).

The length of stay and inpatient burden in inpatients with different psoriasis subtypes.

Background: Heavy disease burden of psoriasis has been indicated by previous studies. However, the cost of care and length of stay (LOS) in inpatients with different psoriasis subtypes were rarely addressed. This study aimed to investigate the cost of care and LOS in Chinese patients with different psoriasis types and to clarify the independent factors affecting LOS. Methods: We conducted a cross-sectional study by enrolling patients with psoriasis who were hospitalized between 13 Feb 2017 and 29 Mar 2021. Demographic and clinical characteristics of the patients were collected by reviewing their Electronic Medical Records. Multivariate linear regression was used to estimate the associations with adjustments. Results: A total of 310 adult patients with psoriasis were included (mean cost of care: 13.0±22.3 kCNY; mean LOS: 7.9±4.3 days). Statistically significant differences were found among patients with different psoriasis subtypes in LOS (P<0.001) but not in the cost of care (P=0.530). Relative to psoriasis vulgaris, pustular psoriasis (Adjusted coefficient: 2.37, 95% confidence interval (CI): 0.87-3.87) and erythrodermic psoriasis (Adjusted coefficient: 2.92, 95%CI: 1.38-4.47) were significantly associated with an increased LOS. Meanwhile, respiratory tract infections (Adjusted coefficient: 1.60, 95%CI: 0.11-3.10) also significantly increased the LOS. On the contrary, a decreased LOS was found in psoriatic arthritis patients treated with TNF-alpha inhibitors (Adjusted coefficient: -2.21, 95%CI: -4.37 to -0.05). Conclusions: LOS differed significantly among different psoriasis subtypes while the inpatient burden for a single hospitalization was alike. Infection is an important factor associated with a longer LOS. TNF-alpha inhibitors evidently reduced the total hospital stay period for patients with psoriatic arthritis.

The Duration and Determinants of Anti-SARS-CoV-2 Immunoglobulin G in Cancer Patients with SARS-CoV-2 Infection: A Longitudinal Study.

Patients with cancer have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and a high case-fatality rate. The duration of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies in cancer patients following SARS-CoV-2 infection has not been reported previously. We conducted a longitudinal study at a cancer center in Wuhan, China to determine the duration of the humoral immune response following SARS-CoV-2 infection in cancer patients and to determine factors associated with a short duration (< 6 months) of anti-SARS-CoV-2 immunoglobulin G (IgG). Of 2139 cancer patients screened, 78 with confirmed SARS-CoV-2 infection were included in this study. SARS-CoV-2 IgG antibodies were present for < 6 months in 39.7% of these patients. In addition, patients who received chemotherapy were more likely to have a short duration of anti-SARS-CoV-2 IgG (odds ratio 5.31, 95% confidence interval 1.09-26.02, P < 0.05). Our study suggests that cancer patients, especially those who were receiving chemotherapy, have a shorter anti-SARS-CoV-2 IgG duration following infection and therefore, should be prioritized for vaccination.

Analysis of carcinogenic signaling networks in endometrial cancer identifies RAB17 as a potential target.

Endometrial cancer is one of the most common malignancies in postmenopausal women. Several potential therapeutic targets have been investigated in current research, but few have been used clinically. Therefore, further investigating the potential pathogenesis of endometrial cancer and new effective therapeutic targets for endometrial malignancies is still necessary. Our study used a The Cancer Genome Atlas dataset and two Gene Expression Omnibus datasets for weighted gene coexpression network analysis to identify important genes associated with the histological grades of endometrial cancer. In addition, we performed gene set enrichment analysis on the three datasets and found that abnormally activated signaling pathways and metabolic pathways are the main biological behaviors of endometrial cancer. Moreover, we further used different algorithms and identified the RAB17 gene as a potential study object. To further illustrate the potential role of the genes we analyzed in clinical and cellular aspects, we performed a clinical correlation analysis. Finally, we demonstrated the important roles and mechanisms of the RAB17 gene in the cell cycle, proliferation, and metastasis of endometrial cancer. Using repeated database analysis and cell-level assays, we propose RAB17 as a potential target gene for endometrial cancer for further study.

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models.

Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

An integrated autophagy-related gene signature predicts prognosis in human endometrial Cancer.

BACKGROUND: Globally, endometrial cancer is the fourth most common malignant tumor in women and the number of women being diagnosed is increasing. Tumor progression is strongly related to the cell survival-promoting functions of autophagy. We explored the relationship between endometrial cancer prognoses and the expression of autophagy genes using human autophagy databases. METHODS: The Cancer Genome Atlas was used to identify autophagy related genes (ARGs) that were differentially expressed in endometrial cancer tissue compared to healthy endometrial tissue. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were referenced to identify important biological functions and signaling pathways related to these differentially expressed ARGs. A prognostic model for endometrial cancer was constructed using univariate and multivariate Cox, and Least Absolute Shrinkage and Selection Operator regression analysis. Endometrial cancer patients were divided into high- and low-risk groups according to risk scores. Survival and receiver operating characteristic (ROC) curves were plotted for these patients to assess the accuracy of the prognostic model. Using immunohistochemistry the protein levels of the genes associated with risk were assessed. RESULTS: We determined 37 ARGs were differentially expressed between endometrial cancer and healthy tissues. These genes were enriched in the biological processes and signaling pathways related to autophagy. Four ARGs (CDKN2A, PTK6, ERBB2 and BIRC5) were selected to establish a prognostic model of endometrial cancer. Kaplan-Meier survival analysis suggested that high-risk groups have significantly shorter survival times than low-risk groups. The area under the ROC curve indicated that the prognostic model for survival prediction was relatively accurate. Immunohistochemistry suggested that among the four ARGs the protein levels of CDKN2A, PTK6, ERBB2, and BIRC5 were higher in endometrial cancer than healthy endometrial tissue. CONCLUSIONS: Our prognostic model assessing four ARGs (CDKN2A, PTK6, ERBB2, and BIRC5) suggested their potential as independent predictive biomarkers and therapeutic targets for endometrial cancer.

De novo haplotype reconstruction in viral quasispecies using paired-end read guided path finding.

Motivation: RNA virus populations contain different but genetically related strains, all infecting an individual host. Reconstruction of the viral haplotypes is a fundamental step to characterize the virus population, predict their viral phenotypes and finally provide important information for clinical treatment and prevention. Advances of the next-generation sequencing technologies open up new opportunities to assemble full-length haplotypes. However, error-prone short reads, high similarities between related strains, an unknown number of haplotypes pose computational challenges for reference-free haplotype reconstruction. There is still much room to improve the performance of existing haplotype assembly tools. Results: In this work, we developed a de novo haplotype reconstruction tool named PEHaplo, which employs paired-end reads to distinguish highly similar strains for viral quasispecies data. It was applied on both simulated and real quasispecies data, and the results were benchmarked against several recently published de novo haplotype reconstruction tools. The comparison shows that PEHaplo outperforms the benchmarked tools in a comprehensive set of metrics. Availability and implementation: The source code and the documentation of PEHaplo are available at https://github.com/chjiao/PEHaplo. Supplementary information: Supplementary data are available at Bioinformatics online.

Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model.

Hearing loss is the main limitation of radiation therapy for vestibular schwannoma (VS), and identifying treatment options that minimize hearing loss are urgently needed. Treatment with bevacizumab is associated with tumor control and hearing improvement in neurofibromatosis type 2 (NF2) patients; however, its effect is not durable and its mechanism of action on nerve function is unknown. We modeled the effect anti-VEGF therapy on neurological function in the sciatic nerve model and found that it improves neurological function by alleviating tumor edema, which may further improve results by decreasing muscle atrophy and increasing nerve regeneration. Using a cranial window model, we showed that anti-VEGF treatment may achieve these effects via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation. It is known that oxygen is a potent radiosensitizer; therefore, we further demonstrated that combining anti-VEGF with radiation therapy can achieve a better tumor control and help lower the radiation dose and, thus, minimize radiation-related neurological toxicity. Our results provide compelling rationale for testing combined therapy in human VS.

Optimal Rate Schedules with Data Sharing in Energy Harvesting Communication Systems.

Despite the abundant research on energy-efficient rate scheduling polices in energy harvesting communication systems, few works have exploited data sharing among multiple applications to further enhance the energy utilization efficiency, considering that the harvested energy from environments is limited and unstable. In this paper, to overcome the energy shortage of wireless devices at transmitting data to a platform running multiple applications/requesters, we design rate scheduling policies to respond to data requests as soon as possible by encouraging data sharing among data requests and reducing the redundancy. We formulate the problem as a transmission completion time minimization problem under constraints of dynamical data requests and energy arrivals. We develop offline and online algorithms to solve this problem. For the offline setting, we discover the relationship between two problems: the completion time minimization problem and the energy consumption minimization problem with a given completion time. We first derive the optimal algorithm for the min-energy problem and then adopt it as a building block to compute the optimal solution for the min-completion-time problem. For the online setting without future information, we develop an event-driven online algorithm to complete the transmission as soon as possible. Simulation results validate the efficiency of the proposed algorithm.

MEF2D/Wnt/ß-catenin pathway regulates the proliferation of gastric cancer cells and is regulated by microRNA-19.

The underlying molecular pathogenesis in gastric cancer remains poorly unknown. The transcription factor myocyte enhancer factor 2D (MEF2D) participates in the initiation and development of many human cancers. However, its potential roles in gastric cancer have surprisingly not been studied. In present study, we first explored MEF2's expression in gastric cancer, finding that only MEF2D rather than MEF2A, 2B, or 2C was elevated in gastric cancer clinical specimens. Furthermore, immunohistochemical analysis on the tissue samples obtained from 260 patients with gastric cancer revealed that MEF2D expression was significantly associated with the clinical stage, vascular invasion, metastasis, and tumor size. Gastric cancer patients with MEF2D expression showed a significantly shorter overall survival time compared with that of patients lacking of MEF2D. Multivariate analysis revealed that MEF2D expression was an independent prognostic factor for overall survival. These results indicated that MEF2D was a prognostic marker for gastric cancer. Notably, MEF2D silencing was able to reduce the proliferation and survival of gastric cancer cells. Further study revealed that MEF2D suppression significantly inactivated the oncogenic Wnt/ß-catenin pathway. Downregulation of MEF2D inhibited the tumorigenesis of gastric cancer cells in nude mice. Finally, MEF2D is a direct target of miR-19, which was found to be decreased in gastric cancer clinical specimens. Collectively, we found that miR-19/MEF2D/Wnt/ß-catenin regulatory network contributes to the growth of gastric cancer, hinting a new promising target for gastric cancer treatment.

Correlations Between Radiation Dose in Bone Marrow and Hematological Toxicity in Patients With Cervical Cancer: A Comparison of 3DCRT, IMRT, and RapidARC.

OBJECTIVE: To comparatively evaluate the hematological toxicity (HT) associated with 3 concurrent chemoradiotherapies that are routinely used to treat cervical cancer, including 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiation therapy (IMRT), and RapidARC and to establish a new normal tissue complication probability model of bone marrow (BM) to predict HT in cervical cancer patients undergoing concurrent chemoradiotherapy. METHODS: Patients with cervical cancer (N = 100) who received concurrent cisplatin and whole-pelvic radiotherapy were enrolled in this study. Dosimetric parameters (including V10, V20, V30, and V40 and mean doses to the pelvic bone) and HT were analyzed. RESULTS: The V20, V30, and V40 and mean doses to the BM were lower in the IMRT and RapidARC groups than in the 3DCRT group, and the RapidARC group had higher V10 and V40 and mean values than the IMRT group. The V20, V30, and V40 and the mean dose to the pelvic bone were positively correlated with HT. Generalized linear normal tissue complication probability models of white blood cell (WBC) and absolute neutrophil cell (ANC) nadirs and BM V20 were established as follows: WBC nadir = 3.382 - 4.056 • V20 + 0.295 • baseline of WBC (adjusted R = 0.246, F = 15.847) and ANC nadir = 2.438 - 2.780 • V20 + 0.233 • baseline of ANC (adjusted R = 0.236, F = 16.282). CONCLUSIONS: This study suggests that IMRT results in milder hematological toxicity than either 3DCRT or RapidARC. Dosimetric parameters were associated with the incidence of HT in cervical cancer patients who received concurrent chemoradiotherapies.

The role of BATF2 deficiency in immune microenvironment rearrangement in cervical cancer - New biomarker benefiting from combination of radiotherapy and immunotherapy.

Despite the significant progress in immunotherapy for certain cancers, including cervical cancer, most patients remain unresponsive or derive limited benefits from combined radiotherapy and chemotherapy. The factors underlying treatment resistance are unknown and there are few reliable predictive biomarkers. BATF2 is a member of the basic leucine zipper transcription factor family and is involved in immune response and immune cell development. However, the role of BATF2 in the immune microenvironment of patients with cervical cancer after radiotherapy remains unclear. In this study, immunohistochemistry and multicolour immunofluorescence analyses of patient tumor samples were used to assess BATF2 expression. We found that cervical cancer patients with high BATF2 expression had higher infiltration levels of CD4+ T cells, CD8+ T cells, and macrophages within the tumor than those with low expression levels. Furthermore, BATF2 expression was positively correlated with the prognosis of patients after concurrent chemoradiotherapy. A wild-type mouse model with BATF2-knockdown U14 cell-derived subcutaneous tumors and a Batf2-/- mouse model with wild-type U14 cell-derived subcutaneous tumors were used to assess CD8+ T cell infiltration and function. As expected, the knockdown of BATF2 in the U14 cell line substantially promoted tumor growth, which was mediated by a reduction in CD8+ T cell infiltration and antitumor function in vivo. Additionally, the Batf2-/- mouse model demonstrated that host BATF2 is also involved in controlling tumor growth. Furthermore, the combination of radiotherapy and anti-PD-1 therapy showed synergistic antitumour effects. These findings collectively suggest that BATF2 may serve as a potent positive regulator of the tumor immune microenvironment of cervical cancer after radiotherapy, and has the potential to be a prognostic biomarker to guide the application of a combination of radiotherapy and immunotherapy.

Simultaneous Enhancement of Strength and Sulfide Stress Cracking Resistance of Hot-Rolled Pressure Vessel Steel Q345 via a Quenching and Tempering Treatment.

Sulfide stress cracking (SSC) failure is a main concern for the pressure vessel steel Q345 used in harsh sour oil and gas environments containing hydrogen sulfide (H2S). Methods used to improve the strength of steel usually decrease their SSC resistance. In this work, a quenching and tempering (Q&T) processing method is proposed to provide higher strength combined with better SSC resistance for hot-rolled Q345 pressure vessel steel. Compared to the initial hot-rolled plates having a yield strength (YS) of ~372 MPa, the Q&T counterparts had a YS of ~463 MPa, achieving a remarkable improvement in the strength level. Meanwhile, there was a resulting SSC failure in the initial hot-rolled plates, which was not present in the Q&T counterparts. The SSC failure was not only determined by the strength. The carbon-rich zone, residual stress, and sensitive hardness in the banded structure largely determined the susceptibility to SSC failure. The mechanism of the property amelioration might be ascribed to microstructural modification by the Q&T processing. This work provides an approach to develop improved strength grades of SSC-resistant pressure vessel steels.

Primary intracranial small cell carcinoma: a case report and review of the literature.

BACKGROUND: Extrapulmonary small cell carcinoma is a distinct clinicopathological entity accounting for only 2.5-4% of small cell carcinomas. Here we present a case of primary intracranial small cell carcinoma. CASE REPORT: A 69-year-old woman with an isolated brain lesion presented with progressive headaches, confusion, nausea, and vomiting. A magnetic resonance imaging scan of the brain revealed a 4 × 3 × 5-cm solitary cystic tumor in the right frontoparietal lobe, accompanied by a midline shift. The mass was resected and pathologically proven to be a small cell carcinoma. The patient was given adjuvant radiotherapy but refused any chemotherapy. At the 12-month follow-up the patient was alive and well. CONCLUSION: Primary intracranial small cell carcinoma presenting as an isolated lesion is extremely rare. While there are no standard treatment guidelines for these patients, the authors believe multimodality treatment including tumorectomy and postoperative radiotherapy should be recommended.

Emerging role of deubiquitination modifications of programmed death-ligand 1 in cancer immunotherapy.

Immune evasion is essential for carcinogenesis and cancer progression. Programmed death-ligand 1 (PD-L1), a critical immune checkpoint molecule, interacts with programmed death receptor-1 (PD-1) on immune cells to suppress anti-tumor immune responses. In the past decade, antibodies targeting PD-1/PD-L1 have tremendously altered cancer treatment paradigms. Post-translational modifications have been reported as key regulators of PD-L1 expression. Among these modifications, ubiquitination and deubiquitination are reversible processes that dynamically control protein degradation and stabilization. Deubiquitinating enzymes (DUBs) are responsible for deubiquitination and have emerged as crucial players in tumor growth, progression, and immune evasion. Recently, studies have highlighted the participation of DUBs in deubiquitinating PD-L1 and modulating its expression. Here, we review the recent developments in deubiquitination modifications of PD-L1 and focus on the underlying mechanisms and effects on anti-tumor immunity.

Surface Performance of Nano-CrN/TiN Multi-Layered Coating on the Surface of Ti Alloy.

Surface coating has been widely used to ameliorate the surface properties of Ti alloys. In this study, high-power pulsed magnetically controlled sputtering technology was used to successfully prepare a nano-CrN/TiN multi-layered coating on the surface of a TC4 Ti alloy. The surface of the obtained coating was uniform, dense, and free of obvious defects. With the decrease in modulation period, the optimal growth of the nano-CrN/TiN multi-layered coating was changed from a (220) crystal surface to (111) and a (200) crystal surface. Compared to the single-layered CrN or TiN coating, the nano-multi-layered coating had higher hardness and lower wear rate. Furthermore, the hardness and the wear resistance increased with the decrease in the modulation period. This presented an optimal modulation period of 6 nm. Meanwhile, the resistance of the obtained coating to high-temperature oxidation at 800 °C was also significantly improved.

Insights into the characteristics of primary radioresistant cervical cancer using single-cell transcriptomics.

Radioresistance is a major cause of radiotherapy failure among patients with cervical cancer (CC), the fourth most common cause of cancer mortality in women worldwide. Traditional CC cell lines lose intra-tumoral heterogeneity, posing a challenge for radioresistance research. Meanwhile, conditional reprogramming (CR) maintains intra-tumoral heterogeneity and complexity, as well as the genomic and clinical characteristics of original cells and tissues. Three radioresistant and two radiosensitive primary CC cell lines were developed under CR conditions from patient specimens, and their characteristics were verified via immunofluorescence, growth kinetics, clone forming assay, xenografting, and immunohistochemistry. The CR cell lines had homogenous characteristics with original tumor tissues and maintained radiosensitivity in vitro and in vivo, while also maintaining intra-tumoral heterogeneity according to single-cell RNA sequencing analysis. Upon further investigation, 20.83% of cells in radioresistant CR cell lines aggregated in the G2/M cell cycle phase, which is sensitive to radiation, compared to 38.1% of cells in radiosensitive CR cell lines. This study established three radioresistant and two radiosensitive CC cell lines through CR, which will benefit further research investigating radiosensitivity in CC. Our present study may provide an ideal model for research on development of radioresistance and potential therapeutic targets in CC.

Cancer-Associated Fibroblasts Exposed to High-Dose Ionizing Radiation Promote M2 Polarization of Macrophages, Which Induce Radiosensitivity in Cervical Cancer.

Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the interactions between TAMs and CAFs in the context of ionizing radiation are not fully understood. This study was undertaken to investigate whether M2 macrophages induce radioresistance in cervical cancer and to explore the TAMs' phenotypic transformation after IR and its underlying mechanisms. The radioresistance of cervical cancer cells was enhanced after being co-cultured with M2 macrophages. TAMs tended to undergo M2 polarization after high-dose irradiation, which was strongly associated with CAFs in both mouse models and patients with cervical cancer. Additionally, cytokine and chemokine analysis was performed to find that high-dose irradiated CAFs promoted macrophage polarization towards the M2 phenotype through chemokine (C-C motif) ligand 2. Collectively, our results highlight the crucial role that high-dose irradiated CAFs play in the regulation of M2 phenotype polarization, which ultimately induces radioresistance in cervical cancer.