Objective: To clarify the clinical characteristics and pathogenic analysis after lower respiratory tract infection in patients with advanced lung cancer under different treatments.

Methods: A retrospective analysis was adopted to collect 94 cases of patients with advanced lung cancer combined with lower respiratory tract infection from January 1, 2018 to December 1, 2020. Seventy-four cases were male and 20 cases were female. According to the different treatments, the patients were divided into 43 cases in the chemotherapy group and 51 cases in the chemoradiotherapy group. The pathogenic and serological indexes were compared between the two groups to provide ideas for the application of antibiotics.

Results: In the comparison of general clinical data, the chemotherapy group had a shorter hospital stay than the chemoradiotherapy group and a higher body mass index level than the chemoradiotherapy group (p < 0.05). In the comparison of serological indicators, procalcitonin, high-sensitive C-reactive protein, erythrocyte sedimentation rate, and neutrophil percentage were lower in the chemotherapy group, and the lymphocyte was higher than that in the chemoradiotherapy group (p < 0.05). There was no difference in hemoglobin, albumin, creatinine, and alanine transaminase between the two groups (p > 0.05). In the comparison of pathogenicity, the chemotherapy group was more likely to have combined viral infections, while the chemoradiotherapy group was more likely to have Gram-negative bacterial infections (p < 0.05). There was no difference between the two groups in terms of fungal infections (p > 0.05). Besides, the chemoradiotherapy group was more likely to have combined infections (p > 0.05).

Conclusion: Patients with advanced lung cancer treated with chemoradiotherapy have a relatively poor prognosis after developing lower respiratory tract infections and are more likely to have mixed infections. Antibiotics need to be applied as early as possible. The common pathogens should be covered. Antiviral and antifungal drugs can be added as appropriate, and drug sensitivity tests should be completed as early as possible.

Objective: This single-center, prospective, observational study was designed to investigate the toxicities, patient-reported outcome (PRO), and dosimetric analysis of whole breast ultrafractionation radiotherapy (RT) after breast-conserving surgery (BCS) in early breast cancer (BC).

Patients and methods: Patients diagnosed with BC stage I, II and treated with BCS were enrolled. A dose of 26 Gray (Gy) in five fractions was prescribed to the whole breast and tumor bed. Clinical endpoints included toxicities, PRO, and dosimetric analysis. PRO was measured by the European Organization for Research and Treatment of Cancer general quality of life questionnaire (EORTC QLQ-C30) and the BC-specific questionnaire (EORTC QLQ-BR23) questionnaires.

Results: Between January 2022 and June 2023, 62 female patients were enrolled. The median age was 45 years. Most patients (83.9%) were diagnosed with pathological stage I disease. The median planning target volume (PTV) was 456.4 mL. The minimum, maximum, and mean doses, and D₉₅ (dose of PTV irradiated volume more than 95%) to PTV were 20.2, 28.8, 27.2, and 26.3 Gy, respectively. The median mean lung dose and percentage lung volume receiving 8 Gy (V₈) were 3.6 Gy and 13.4%, respectively. The median mean heart dose, V_1.5 (percentage of organ volume irradiated with 1.5 Gy or higher), and V₇ (percentage of organ volume irradiated with 7 Gy or higher) were 0.6 Gy, 6.8%, and 0.4%, respectively. Cosmetic effects before RT showed no obvious differences compared to that post RT. No toxicities of grade 3 or higher occurred. Five patients had asymptomatic radiation pneumonia (grade 1), and 12 patients had radiation dermatitis (grade 1). No factor was significantly related to radiation dermatitis or radiation pneumonia. For the EORTC QLQ-C30 and QLQ-BR23 questionnaires, all function and symptom scores before RT had no significant differences compared with that after RT, 1–2 months after RT, and 3–4 months after RT. Ultrafractionation RT did not worsen PRO. The 1-year crude local control was 100%.

Conclusion: Whole breast ultrafractionation RT after BCS in early BC has no severe toxicities and does not affect PRO. These results need to be further validated with a longer follow-up and a larger sample size.

As a major kind of cell surface adhesion molecules with signal transduction function, integrins play a major role in tumorigenesis and tumor progression. The role of integrins in tumor cells and the tumor microenvironment has been extensively revealed. Among the integrin family, integrin αvβ3 is the most studied integrin in the past 20 years. Plenty of preclinical and clinical studies have been conducted, which showed clinical benefits of targeting integrin αvβ3 in tumor imaging and treatment. Currently, the focus of interest is gradually shifting from integrin αvβ3 toward other integrin subtypes. Integrin α6 is expressed in many malignant tumors, such as colorectal cancer, head and neck squamous cell carcinoma, breast cancer, pancreatic cancer, and liver cancer, and its expression is correlated with poor survival of the patients. Recent studies have shown that tumor molecular imaging agents and therapeutic drugs targeting integrin α6 have excellent safety and efficacy in preclinical mouse models, encouraging clinical translation of this promising target. In this review, we briefly overview the physiological and pathological function of integrin α6 and highlight the recent advances in integrin α6-targeted imaging and therapeutics in tumors.

Background: The aims of this study were to evaluate the prognostic ability of the neoadjuvant rectal (NAR) score and to develop and validate a nomogram based on the NAR for patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT).

Methods: In total, 307 patients, including 230 patients from the primary cohort and 77 from the external cohort, were enrolled across the two centers. The associations of the NAR score with the tumor response, tumor control, and clinicopathological parameters were analyzed. Survival analysis was performed in the primary and external cohorts using Kaplan‒Meier curves. Univariate and multivariate analyses were performed to evaluate the prognostic factors. The NAR‐based nomogram was developed in the primary cohort and validated in the external cohort using the concordance index (C‐index), calibration plots, and decision curve analyses (DCAs).

Results: Kaplan‒Meier survival analysis revealed that the disease‐free survival (DFS) and overall survival (OS) of the NAR > 16 group were significantly lower than those of the NAR ≤ 16 group (p < 0.001). Multivariate Cox regression analysis identified the NAR score as an independent prognostic factor for both DFS (hazard ratio [HR] = 2.484, 95% confidence interval [CI]: 1.159−5.323, p = 0.019) and OS (HR = 4.633, 95% CI: 1.076−19.941, p = 0.04). Calibration plots and DCAs showed that NAR‐based nomograms for DFS and OS were consistent and useful in clinical practice. Moreover, the C‐indexes of the NAR‐based nomograms were better than those of the other variables in both the primary and external cohorts.

Conclusion: Our study validates the prognostic role of the NAR score for DFS and OS. The NAR‐based nomogram for OS could accurately predict the outcome of LARC patients by stratifying the risk score accordingly.

Gastric cancer (GC) is one of the most common malignancies globally, the occurrence of which undergoes a multistage chronic evolutionary process. It is a great public health issue to deeply understand the mechanisms of GC development and factors affecting the evolution of gastric lesions. Helicobacter pylori infection has been identified as one of the main factors for gastric carcinogenesis and microbial dysbiosis. With the advances in molecular biology techniques, other gastric microbes besides H. pylori have been observed to play an essential role in the development of GC. Previous animal model studies suggested that specific and critical microbes in the stomach can accelerate the malignant transformation of gastric mucosa and the progression of gastric lesions to GC. Recently, the composition of human gastric microbiota has been investigated from stages of precancerous lesions to GC, including characteristics of gastric microbiota diversity, lesion‐associated differential microbes, predicted microbiota‐related functions, microbiota interactions, and microbial mechanisms in gastric carcinogenesis. In this review, we provide an overview of the gastric microbiota, summarize current studies exploring the roles of microbiota in gastric carcinogenesis, and illustrate the significance and prospects of integrative multiomics analysis combined with the microbiome in gastric carcinogenesis.

Pancreatic cancer is one of the deadliest malignancies, with limited effectiveness of standard therapies, resulting in little improvement in the 5-year survival rate over the past few decades. However, advanced radiotherapy techniques and emerging treatment modalities, such as immunotherapy and targeted therapy, are showing tremendous potential as effective treatment options for pancreatic cancer patients who were previously considered incurable. This review summarizes the current advances and challenges in pancreatic cancer treatment strategies and proposes further optimization directions, aiming to provide insights into the cure of incurable pancreatic cancer.

During the process of carcinogenesis and tumor progression, various molecular alternations occur in different omics levels. In recent years, multiomics approaches including genomics, epigenetics, transcriptomics, proteomics, metabolomics, single-cell omics, and spatial omics have been applied in mapping diverse omics profiles of cancers. The development of high-throughput technologies such as sequencing and mass spectrometry has revealed different omics levels of tumor cells or tissues separately. While focusing on a single omics level results in a lack of accuracy, joining multiple omics approaches together undoubtedly benefits accurate molecular subtyping and precision medicine for cancer patients. With the deepening of tumor research in recent years, taking pathological classification as the only criterion of diagnosis and predicting prognosis and treatment response is found to be not accurate enough. Therefore, identifying precise molecular subtypes by exploring the molecular alternations during tumor occurrence and development is of vital importance. The review provides an overview of the advanced technologies and recent progress in multiomics applied in cancer molecular subtyping and detailedly explains the application of multiomics in identifying cancer driver genes and metastasis-related genes, exploring tumor microenvironment, and selecting liquid biopsy biomarkers and potential therapeutic targets.

Background: Hepatocellular carcinoma (HCC) is a common disease in human history and one of the main causes of cancer-related death. Insufficient oxygen supply in the tumor microenvironment forces cancer cells to survive in a mild hypoxia environment. Fibroblast growth factor 21 (FGF21), a member of the FGF family, has become the focus of public attention due to its outstanding achievements in diabetes and lipid lowering. However, the mechanism of FGF21 in HCC remains unclear.

Objective: The aims of this study were to clarify whether or not FGF21 could increase the sensitivity of sorafenib (SORA) to HCC under hypoxia and explore the possible mechanism.

Methods: In this study, by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide cell viability test, plate clone formation test, western blot analysis, Hoechst/propidium iodide double staining experiment, flow cytometry, quantitative reverse transcription polymerase chain reaction, and subcutaneous tumor transplantation in mice, we studied the effects of recombinant human FGF21 combined with SORA on hepatoma cells in vitro and in vivo. FGF21 could enhance the phosphorylation of mothers against decapentaplegic homolog 3 (Smad3) under anaerobic conditions. When combined with SORA, FGF21 could increase the sensitivity of hepatoma cells to SORA and inhibit the growth and migration of hepatoma cells.

Results: FGF21 may increase the sensitivity of HCC to SORA by enhancing the phosphorylation of Smad3 through the phosphatidylinositol 3-kinase/protein kinase B pathway under hypoxia.

Conclusion: Our study suggested the possibility of combination therapy for SORA and FGF21 on HCC.

Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common malignancy worldwide. However, very few established diagnostic biomarkers for HNSCC have been universally applied in clinical practice. Recently, much attention has been paid to extracellular vesicles (EVs) regarding their roles as cancer biomarkers because EVs carry plentiful cargoes, including lipids, proteins, nucleic acids, and metabolites. In HNSCC, several molecules carried by EVs, which are derived from peripheral blood and saliva, have been implicated to be effective in cancer detection, staging, treatment planning, response monitoring, and prognosis prediction. Although several EV molecules have been identified to be significantly correlated with a set of clinicalpathological parameters of HNSCC, several key limitations need to be resolved before the clinical application of EVs as carriers of biomarkers in HNSCC. In this review, we discuss current knowledge in the literature regarding EV-based biomarkers in HNSCC, emphasizing current limitations of their clinical applications.

Background: The relationship between the regression and prognosis of melanoma has been debated for years. When competing-risk events are present, using traditional survival analysis methods may induce bias in the identified prognostic factors that affect patients with regressive melanoma.

Methods: Data on patients diagnosed with regressive melanoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) database during 2000–2019. Cumulative incidence function and Gray’s test were used for the univariate analysis, and the Cox proportional-hazards model and the Fine–Gray model were used for the multivariate analysis.

Results: A total of 1442 eligible patients were diagnosed with regressive melanoma, including 529 patients who died: 109 from regressive melanoma and 420 from other causes. The multivariate analysis using the Fine–Gray model revealed that SEER stage, surgery status, and marital status were important factors that affected the prognosis of regressive melanoma. Due to the existence of competing-risk events, the Cox model may have induced biases in estimating the effect values, and the competing-risks model was more advantageous in the analysis of multipleendpoint clinical survival data.

Conclusion: The findings of this study may help clinicians to better understand regressive melanoma and provide reference data for clinical decisions.

Basic research on heavy ion cancer therapy such as radiobiology, medical physics, and therapeutic technique has been conducted at the Institute of Modern Physics (IMP), Chinese Academy of Sciences since 1995. Based on the achievements acquired in the basic research and the requirements for a heavy ion accelerator for radiotherapy purposes, a dedicated heavy ion therapy facility named Heavy Ion Medical Machine (HIMM) was designed at IMP and constructed in Wuwei, China. The HIMM facility consists of two electron cyclotron resonance ion sources, one cyclotron as the injector and one synchrotron as the main accelerator, and four different treatment rooms equipped with passive or active beam delivery systems, and accelerates carbon ions up to 400 MeV/u. After the performance inspection of HIMM organized by the National Medical Device Inspection Center, preclinical tests like cell and animal radiobiological experiments and dosimetric verification using anthropomorphic phantoms for elucidating the biophysical properties of the carbon ion beams provided by HIMM were carried out. According to the Chinese medical device regulations, a clinical trial in which 46 tumor patients were recruited and two hospitals participated was conducted in the HIMM facility, aiming at evaluating the treatment safety and short-term efficacy of the medical device. The success of the clinical trial helped the HIMM facility be authorized by the Chinese government as a class III medical device. In this paper, all the aspects mentioned above are introduced and discussed, and implications for future improvements are also given.

Background: Cervical cancer is a highly aggressive cancer that seriously affects the physical and mental health and quality of life of women, especially for women in developing countries. Therefore, cervical cancer has always been the focus of research, and in recent years, various studies on cervical cancer have emerged one after another.

Methods: Our study aimed to illustrate the development trends in cervical cancer research in China from 2013 to 2022 and compare the findings with studies in other parts of the world during the same period by using bibliometric analysis and the Science Citation Index Expanded. Literature data were analyzed and visualized by using CiteSpace and VOSviewer.

Results: The results show that the number of articles on cervical cancer has increased in recent years, among which articles on the pathogenesis and epidemiological characteristics of cervical cancer account for the majority. The research in China has developed rapidly in recent years, but there is still a certain gap compared with other developed countries.

Conclusion: Bibliometric and visualization analyses offer a unique and objective perspective in the field of cervical cancer and may assist scholars in identifying new research directions.

Background: Population-based cancer survival is a key metric in evaluating the overall effectiveness of health services and cancer control activities. Advancement in information technology enables accurate vital status tracking through multi-source data linkage. However, its reliability for survival estimates in China is unclear.

Methods: We analyzed data from Dalian Cancer Registry to evaluate the reliability of multi-source data linkage for population-based cancer survival estimates in China. Newly diagnosed cancer patients in 2015 were included and followed until June 2021. We conducted single-source data linkage by linking patients to Dalian Vital Statistics System, and multi-source data linkage by further linking to Dalian Household Registration System and the hospital medical records. Patient vital status was subsequently determined through active follow-up via telephone calls, referred to as comprehensive follow-up, which served as the gold standard. Using the cohort method, we calculated 5-year observed survival and age-standardized relative survival for 20 cancer types and all cancers combined.

Results: Compared to comprehensive follow-up, single-source data link-age overestimated 5-year observed survival by 3.2% for all cancers combined, ranging from 0.1% to 8.6% across 20 cancer types. Multi-source data linkage provided a relatively complete patient vital status, with an observed survival estimate of only 0.3% higher for all cancers, ranging from 0% to 1.5% across 20 cancer types.

Conclusion: Multi-source data linkage contributes to reliable population-based cancer survival estimates in China. Linkage of multiple databases might be of great value in improving the efficiency of follow-up and the quality of survival data for cancer patients in developing countries.

Objective: To highlight the incidence and management of acute coronary syndrome (ACS) in patients with gastric cancer undergoing immune checkpoint inhibitor (ICI) therapy, emphasizing the need for early detection and intervention in this high-risk population.

Patients and methods: We presented a case of a 71-year-old male patient with poorly differentiated adenocarcinoma of the gastric antrum, clinical stage cT4N2M0, phase III, with no prior history of chronic diseases or cardiovascular risk factors. The patient was treated with a combination of ICI therapy (sintilimab) and chemotherapy using the albumin-bound paclitaxel combined with S1 regimen. Following therapy, he developed symptoms and diagnostic findings consistent with ACS, which was managed with percutaneous coronary stenting.

Results: The patient’s presentation with ACS during ICI therapy underscored the potential cardiovascular risks associated with cancer treatments, particularly in patients without traditional cardiovascular risk factors. Management involved collaboration between oncologists and cardiologists, leading to successful coronary stenting and continuation of antitumor therapy.

Conclusion: ACS is a significant risk in patients with malignancies undergoing ICI therapy, even in those without prior cardiovascular disease. Early recognition and management of ACS in this context are crucial to enable the continuation of cancer treatment and improve patient outcomes. This case underscores the importance of interdisciplinary collaboration in managing complex patients with concurrent cancer and cardiovascular disease.

Background: Immunotherapy combined with chemotherapy has been approved as first-line therapy for small cell lung cancer (SCLC) due to the survival benefit in randomized controlled trials. However, predicting its efficacy remains a challenge in the absence of currently available biomarkers.

Methods: A total of 140 individuals with SCLC who received immunotherapy were evaluated retrospectively. These patients were split into two distinct cohorts, the discovery cohort (80% of the total, n = 112) and the validation cohort (20% of the total, n = 28). The objective response rate (ORR), disease control rate (DCR), and responder (progression-free survival [PFS] > 6 months) were all predicted using neural networks.

Results: We developed predictive models for three clinical outcomes. ORR scored 0.8964 area under the receiver operating characteristic curve (AUC) in the discovery cohort and 0.8421 AUC in the validation cohort. DCR model had AUC of 0.8618 in the discovery cohort and AUC of 0.7396 in the validation cohort. The responder model had AUC of 0.8116 in the discovery cohort and AUC of 0.7041 in the validation cohort. The models were then compressed into a doctor-friendly tool.

Conclusion: These neural network-based models, which are based on routine clinical characteristics, accurately predict the efficacy of immunotherapy in patients with SCLC, particularly in terms of ORR.

Background: This study aimed to explore the impact of patient-specific factors on the effectiveness of platinum-based chemotherapy in ovarian cancer patients. Specifically, we investigated the relationship between estrogen receptor (ER) and progesterone receptor (PR) expression levels and platinum sensitivity, and how this influenced treatment outcomes and prognosis. We conducted a survival analysis on patients who underwent surgical treatment for serous ovarian cancer and received platinum-based adjuvant therapies.

Methods: This study was a retrospective observational analysis of 171 patients with high-grade serous ovarian cancer. We extracted and analyzed the patients’ clinical data, focusing on platinum sensitivity concerning hormone receptor expression. We also assessed survival outcomes based on receptor expression and platinum resistance.

Results: Our findings revealed that 78.4% (n = 134) of the patients were platinum-sensitive, while 21.6% (n = 37) were platinum-resistant. The expression of hormone receptors showed significant associations with platinum sensitivity, particularly among ER-positive patients (p<0.05). Age, disease stage, preoperative carbohydrate antigen 125 (CA125) levels, and residual tumor size were identified as notable factors influencing both progression-free survival (PFS) and overall survival (OS). In terms of PFS, 88.5% of patients remained free from disease progression after one year, but this percentage dropped to 21% after five years. The average duration of PFS was 35.3 months. As for OS, 93.5% of patients were still alive after one year, but this percentage decreased to 50.5% after five years. The average survival duration was 64 months. Furthermore, platinum resistance was found to be a significant risk factor for disease progression, with a more than fivefold increase in risk (p < 0.001).

Conclusion: Our study identified disease stage progression, ER negativity, and platinum resistance as the primary factors influencing OS. We also found that ER and PR expression played a crucial role in determining the sensitivity to platinum-based chemotherapy in patients with serous ovarian cancer.

Background: The effects of programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICIs) in patients with squamous and nonsquamous non-small cell lung cancer (NSCLC) remain controversial. We conducted a meta-analysis to summarize the existing evidence on this topic.

Methods: We searched PubMed, Medline, and Embase for studies published before December 1, 2022, comparing PD-1/PD-L1 ICIs with docetaxel in squamous and nonsquamous NSCLC patients in any language. The different hazard ratio (HR) values for overall survival (OS) and progression-free survival (PFS) were calculated in this study.

Results: A total of seven studies were identified. In a summary analysis of all studies, the HR values of OS in patients with nonsquamous and squamous NSCLC were 0.73, 95% confidence interval (CI): 0.67–0.79 and 0.70, 95% CI: 0.62–0.79, respectively. In patients with PD-L1 expression levels of 1% or higher, the HR values of OS in nonsquamous and squamous NSCLC patients were 0.60, 95% CI: 0.49–0.74 and 0.72, 95% CI: 0.54–0.96, respectively. The HR values of OS in nonsquamous and squamous NSCLC patients with PD-L1 expression levels of 5% or higher were 0.46, 95% CI: 0.35–0.59 and 0.55, 95% CI: 0.39–0.79, respectively. In nonsquamous and squamous NSCLC patients with PD-L1 expression levels of 10% or higher, the HR values of OS were 0.42, 95% CI: 0.32–0.54, and 0.53, 95% CI: 0.36–0.78, respectively.

Conclusion: The meta-analysis demonstrated possible evidence that there was different efficacy of PD-1/PD-L1 ICIs on OS in squamous and nonsquamous NSCLC patients with different PD-L1 expression levels. Subgroup analysis showed that there was a greater OS benefit in patients with nonsquamous NSCLC.

Objective: This study aimed to report the treatment and outcomes of a patient with advanced gastric cancer (GC) using a combination of a targeted molecular therapy and chemotherapy.

Patients and methods: A 40-year-old woman presented with abdominal metastatic nodules and peritoneal effusion. Biopsy and cytology identified signet ring cell carcinoma. Ten months after the onset of initial symptoms, gastroscopy confirmed signet ring cell carcinoma of the gastric body. Genetic testing revealed amplification of the fibroblast growth factor receptor (FGFR) gene. Consequently, the patient received FGFR inhibitor pemigatinib in addition to a chemotherapy regimen of albumin paclitaxel plus 5-fluorouracil.

Results: During the treatment, the patient experienced recurrent liver function abnormalities and intestinal obstruction, which were managed with symptom-specific medications and supportive therapies. The combined treatment regimen resulted in a progression-free survival (PFS) period of ten months.

Conclusion: The integration of FGFR inhibitor pemigatinib with standard chemotherapy showed promising results in prolonging PFS in a patient with advanced GC characterized by FGFR gene amplification, despite the occurrence of manageable side effects.

Antigen presentation, as the initial step in inducing the activation of T lymphocytes, plays a crucial role in antitumor response. Studies concentrating on major histocompatibility complex class II (MHC II) molecules and the activated CD4⁺ helper T (Th) cells have gained popularity in light of the past limited efficacy of MHC I-activated CD8⁺ T cells alone. In general, MHC II is canonically expressed by professional antigen-presenting cells (pAPCs), yet attempts to increase antigen presentation by dendritic cell (DC) activation have mostly been unsuccessful. In recent years, a number of studies have found that a variety of cells, including cancer cells, fibroblasts, vascular endothelial cells (VECs), and lymphoid stromal cells (LSCs), are considered amateur APCs (aAPCs) and can express MHC II molecules, which have piqued the interest of researchers. These groups vastly outnumber DCs or macrophages, and it has been confirmed that they also qualify as antigen-presenting complexes that are functionally related to conventional pAPCs. Herein, we will review current research regarding the antigen presentation process of MHC II, its advances in APC surfaces, especially for aAPCs, the special mechanisms of regulation of MHC II on aAPCs, and combination therapy targeting MHC II as a possible treatment strategy in cancer.

Gastric cancer (GC) is a global public health burden, with nearly one million new cases diagnosed each year worldwide. To investigate the risk factors and the prevention strategies for GC, in the past 40 years, a series of epidemiological studies have been carried out in Linqu County, Shandong Province, a high-risk area of GC in China. Here, we briefly review the major efforts of 40-year practices against GC in Linqu County, particularly highlighting a case-control study to identify GC risk factors, a cohort study to determine the associations between the risk factors and the progression of gastric lesions, and an intervention trial to prevent GC development.