Application of dose-gradient function in reducing radiation induced lung injury in breast cancer radiotherapy.

OBJECTIVE: Try to create a dose gradient function (DGF) and test its effectiveness in reducing radiation induced lung injury in breast cancer radiotherapy. MATERIALS AND METHODS: Radiotherapy plans of 30 patients after breast-conserving surgery were included in the study. The dose gradient function was defined as DGH=VDVp3, then the area under the DGF curve of each plan was calculated in rectangular coordinate system, and the minimum area was used as the trigger factor, and other plans were triggered to optimize for area reduction. The dosimetric parameters of target area and organs at risk in 30 cases before and after re-optimization were compared. RESULTS: On the premise of ensuring that the target dose met the clinical requirements, the trigger factor obtained based on DGF could further reduce the V5, V10, V20, V30 and mean lung dose (MLD) of the ipsilateral lung in breast cancer radiotherapy, P < 0.01. And the D2cc and mean heart dose (MHD) of the heart were also reduced, P < 0.01. Besides, the NTCPs of the ipsilateral lung and the heart were also reduced, P < 0.01. CONCLUSION: The trigger factor obtained based on DGF is efficient in reducing radiation induced lung injury in breast cancer radiotherapy.

The dual role of SUSD2 in cancer development.

Sushi domain-containing protein 2 (SUSD2, also known as the complement control protein domain) is a representative and vital protein in the SUSD protein family involved in many physiological and pathological processes beyond complement regulation. Cancer is one of the leading causes of death worldwide. The complex role of SUSD2 in tumorigenesis and cancer progression has raised increasing concerns. Studies suggest that SUSD2 has different regulatory tendencies among different tumors and exerts its biological effects in a cancer type-specific manner; for instance, it has oncogenic effects on breast cancer, gastric cancer, and glioma and has tumor-suppression effects on lung cancer, bladder cancer, and colon cancer. Moreover, SUSD2 can be regulated by noncoding RNAs, its promoter methylation and other molecules, such as Galectin-1 (Gal-1), tropomyosin alpha-4 chain (TPM4), and p63. The therapeutic implications of targeting SUSD2 have already been preliminarily revealed in some malignancies, including melanoma, colon cancer, and breast cancer. This article reviews the role and regulatory mechanisms of SUSD2 in cancer development, as well as its structure and distribution. We hope that this review will advance the understanding of SUSD2 as a diagnostic and/or prognostic biomarker and provide new avenues for the development of novel cancer therapies.

Quantified difference of the collapsed cone convolution (CCC) and Monte Carlo (MC) algorithms based on DVH and gamma analysis for cervical cancer radiation therapy.

OBJECTIVE: To quantify the difference between the (collapsed cone convolution) CCC algorithm and the (Monte Carlo) MC algorithm and remind that the planners should pay attention to some possible uncertainties of the two algorithms when employing the two algorithms. METHODS: Thirty patients' cervical cancer VMAT plans were designed with a Pinnacle TPS (Philips) and divided equally into two groups: the simple group (SG, target volume was only the PTV) and the complex group (CG, target volume included the PTV and PGTV). The plans from the Pinnacle TPS were transferred to the Monaco TPS (Elekta). The plans' parameters all remained unchanged, and the dose was recalculated. Gamma passing rates (GPRs) obtained from dose distribution from Pinnacle TPS compared with that from Monaco TPS with SNC software based on three triaxial planes (transverse, sagittal and coronal). GPRs and DVH were used to quantify the difference between the CCC algorithm in pinnacle TPS and the MC algorithm in Monaco TPS. RESULTS: Among the statistical dose indexes in DVHs from the Pinnacle and Monaco TPSs, there were 7(7/15) dose indexes difference with statistically significant differences in the SG, and 10(10/18) dose indexes difference with statistically significant differences in the CG. With 3%/3 mm criterion, the most (5/6) GPRs were greater than 95% from the SG and CG. But with 2%/2 mm criterion, the most (5/6) GPRs were less than 90% from the two groups. In addition, we found that GPRs were also related to the selected triaxial planes and the complexity of the plan (GPRs varied with the SG and CG). CONCLUSIONS: Obvious difference between the CCC and MC algorithms from Pinnacle and Monaco TPS. DVH maybe better than 2D gamma analysis on quantifying difference of the CCC and MC algorithms. Some attention should be paid to the uncertainty of the TPS algorithm, especially when the indicator on the DVH is at the critical point of the threshold value, because the algorithm used may overestimate or underestimate the DVH indicator.

A systematic mutation analysis of 13 major SARS-CoV-2 variants.

SARS-CoV-2 evolves constantly with various novel mutations. Due to their enhanced infectivity, transmissibility and immune evasion, a comprehensive understanding of the association between these mutations and the respective functional changes is crucial. However, previous mutation studies of major SARS-CoV-2 variants remain limited. Here, we performed systematic analyses of full-length amino acids mutation, phylogenetic features, protein physicochemical properties, molecular dynamics and immune escape as well as pseudotype virus infection assays among thirteen major SARS-CoV-2 variants. We found that Omicron exhibited the most abundant and complex mutation sites, higher indices of hydrophobicity and flexibility than other variants. The results of molecular dynamics simulation suggest that Omicron has the highest number of hydrogen bonds and strongest binding free energy between the S protein and ACE2 receptor. Furthermore, we revealed 10 immune escape sites in 13 major variants, some of them were reported previously, but four of which (i.e. 339/373/477/496) are first reported to be specific to Omicron, whereas 462 is specific to Epslion. The infectivity of these variants was confirmed by the pseudotype virus infection assays. Our findings may help us understand the functional consequences of the mutations within various variants and the underlying mechanisms of the immune escapes conferred by the S proteins.

Effectiveness and safety of glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes: evidence from a retrospective real-world study.

Introduction: Global phase III clinical trials have shown superior hypoglycemic efficacy to insulin and other oral hypoglycemic agents. However, there is a scarcity of real-world data comparing different glucagon-like peptide 1 receptor agonist (GLP-1RA) directly. This study aimed to assess the safety and effectiveness of various GLP-1RA in treating type 2 diabetes mellitus (T2DM) in a real-world clinical setting and identify predictive factors for favorable treatment outcomes. Methods: This was a retrospective, single-center, real-world study. The changes in HbA1c, fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the percentage of participants who achieved HbA1c of <7%, 7%-8%, and ≥ 8% after GLP-1RA treatment was analyzed. The clinical factors that affect the effectiveness of GLP-1RA were analyzed. Results: At baseline, the 249 participants had a mean baseline HbA1c of 8.7 ± 1.1%. After at least three months of follow-up, the change in HbA1c was -0.89 ± 1.3% from baseline. Dulaglutide exerted a more significant hypoglycemic effect than immediate-release exenatide. The percentage of participants who achieved HbA1c<7% was substantial, from 6.0% at baseline to 28.9%. Average body weight decreased by 2.02 ± 3.8 kg compared to baseline. After GLP-1RA treatment, the reduction in SBP was 2.4 ± 7.1 mmHg from baseline. A shorter duration of diabetes and a higher baseline HbA1c level were more likely to achieve a good response in blood glucose reduction. Conclusions: This study provided real-world evidence showing that GLP-1RA significantly improved HbA1c, body weight, and SBP. The results can inform the decision-making about GLP-1RA treatment in daily clinical practice.

RPL35A promotes the progression of cholangiocarcinoma by mediating HSPA8 ubiquitination.

BACKGROUND: Cholangiocarcinoma (CCA) is a biliary epithelial malignant tumor with an increasing incidence worldwide. Therefore, further understanding of the molecular mechanisms of CCA progression is required to identify new therapeutic targets. METHODS: The expression of RPL35A in CCA and para-carcinoma tissues was detected by immunohistochemical staining. IP-MS combined with Co-IP identified downstream proteins regulated by RPL35A. Western blot and Co-IP of CHX or MG-132 treated CCA cells were used to verify the regulation of HSPA8 protein by RPL35A. Cell experiments and subcutaneous tumorigenesis experiments in nude mice were performed to evaluate the effects of RPL35A and HSPA8 on the proliferation, apoptosis, cell cycle, migration of CCA cells and tumor growth in vivo. RESULTS: RPL35A was significantly upregulated in CCA tissues and cells. RPL35A knockdown inhibited the proliferation and migration of HCCC-9810 and HUCCT1 cells, induced apoptosis, and arrested the cell cycle in G1 phase. HSPA8 was a downstream protein of RPL35A and overexpressed in CCA. RPL35A knockdown impaired HSPA8 protein stability and increased HSPA8 protein ubiquitination levels. RPL35A overexpression promoted CCA cell proliferation and migration. HSPA8 knockdown inhibited CCA cell proliferation and migration, and reversed the promoting effect of RPL35A. Furthermore, RPL35A promoted tumor growth in vivo. In contrast, HSPA8 knockdown suppressed tumor growth, while was able to restore the effects of RPL35A overexpression. CONCLUSION: RPL35A was upregulated in CCA tissues and promoted the progression of CCA by mediating HSPA8 ubiquitination.

High-expressed ACAT2 predicted the poor prognosis of platinum-resistant epithelial ovarian cancer.

BACKGROUND: Acetyl-CoA acetyltransferase 2 (ACAT2) is a lipid metabolism enzyme and rarely was researched in epithelial ovarian cancer (EOC). METHODS: ACAT2 expressions were confirmed in two pairs of cell lines (A2780 and A2780/DDP, OVCAR8 and OVCAR8/DDP) from Gene Expression Omnibus database by bioinformatics analysis, and in A2780 and A2780/DDP cell lines by quantitative real-time polymerase chain reaction and western blotting. Tissue samples were stained by immunohistochemistry and scored for ACAT2 expression. The relationships between ACAT2 expression and clinicopathological characteristics were analyzed by χ2 test. The prognosis of ACAT2 was analyzed by the log-rank tests and Cox regression models. RESULTS: ACAT2 was remarkably upregulated in the above drug-resistant cell lines by mRNA (all P < 0.05) and protein expression (P = 0.026) than those in sensitive ones. Patients were classified as ACAT2-high (n = 51) and ACAT2-low (n = 26) according to immunohistochemical score. ACAT2 expression had a significantly inverse correlation with FIGO stage (P = 0.030) and chemo-response (P = 0.041). A marginal statistical significance existed in ACAT2 expression and ascites volume (P = 0.092). Univariate analysis suggested that high-expressed ACAT2 was associated with decreased platinum-free interval (PFI) (8.57 vs. 14.13 months, P = 0.044), progression-free survival (PFS) (14.12 vs. 19.79 months, P = 0.039) and overall survival (OS) (36.89 vs. 52.40 months, P = 0.044). Multivariate analysis demonstrated that ACAT2 expression (hazard ratio = 2.18, 95% confidence interval: 1.15-4.11, P = 0.017) affected OS independently, rather than PFI and PFS. CONCLUSION: The expression of ACAT2 in A2780/DDP and OVCAR8/DDP was higher than the corresponding A2780 and OVCAR8. High-expressed ACAT2 was associated with advanced FIGO stage, chemo-resistance, and decreased PFI, PFS and OS. It was an independent prognostic factor of OS in EOC.

Integrin αvß1 facilitates ACE2-mediated entry of SARS-CoV-2.

Integrins have been suggested to be involved in SARS-CoV-2 infection, but the underlying mechanisms remain largely unclear. This study aimed to investigate how integrins facilitate the ACE2-mediated cellular entry of SARS-CoV-2. We first tested the susceptibility of a panel of human cell lines to SARS-CoV-2 infection using the spike protein pseudotyped virus assay and examined the expression levels of integrins in these cell lines by qPCR, western blot and flow cytometry. We found that integrin αvß1 was highly enriched in the SARS-CoV-2 susceptible cell lines. Additional studies demonstrated that RGD (403-405)→AAA mutant was defective in binding to integrin αvß1 compared to its wild type counterpart, and anti-αvß1 integrin antibodies significantly inhibited the entry of SARS-CoV-2 into the cells. Further studies using mouse NIH3T3 cells expressing human ACE2, integrin αv, integrin ß1, and/or integrin αvß1 suggest that integrin αvß1 was unable to function as an independent receptor but could significantly facilitate the cellular entry of SASR-CoV-2. Finally, we observed that the Omicron exhibited a significant increase in the ACE2-mediated viral entry. Our findings may enhance our understanding of the pathogenesis of SARS-CoV-2 infection and offer potential therapeutic target for COVID-19.

Causal relationship between gut microbiota and thyroid nodules: a bidirectional two-sample Mendelian randomization study.

Objective: Emerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs. Methods: Employing summary statistics from the MiBioGen consortium (n=18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran's Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders. Results: Our findings suggest that certain microbiota, identified as Ruminococcaceae_NK4A214_group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs' development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella_7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs' risk. Discussion: This study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis's relevance. The findings advocate for the integration of GM profiles in TNs' prevention and management, offering a foundation for future research in this domain.

Efficacy and safety of robotic vs. laparoscopic gastrectomy for patients with gastric cancer: systematic review and meta-analysis.

BACKGROUND: The emergence of robotic surgical systems compensated for the technological shortcomings of laparoscopic approaches. However, whether robotic gastrectomy (RG) has better perioperative outcomes and survival than laparoscopic gastrectomy (LG) for gastric cancer is still unclear but increasingly drawing attention. MATERIALS AND METHODS: In this systematic review and meta-analysis, we searched the PubMed, EMBASE, Web of Science, and Cochrane Library as of January 20, 2024 and referenced list of eligible articles for all published studies comparing RG and LG for patients with gastric cancer, Data on study characteristics, individual characteristics, and outcome parameters were extracted. The quality of studies was assessed using the Revised Cochrane risk-of-bias 2 tool and the risk of bias in non-randomized studies of interventions tool. The main outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS: We identified 3641 articles, of which 72 studies (30081 patients) were included in the meta-analysis. Compared with LG, RG was associated with higher OS [hazard ratio (HR)=0.89, 95% CI=0.83 to 0.96), lower rate of overall postoperative complications [odds ratio (OR)=0.77, 95% CI=0.71 to 0.84], longer operating time [mean difference (MD)=35.53, 95% CI=29.23 to 41.83], less estimated blood loss (MD=-37.45, 95% CI=-46.24 to -28.67), a higher number of retrieved lymph nodes (MD=1.88, 95% CI=0.77 to 3.00), faster postoperative recovery, and lower rate of conversion (OR=0.44, 95% CI=0.36 to 0.55). Mortality and DFS were not significantly different between the two groups. The subgroup of meta-analysis results also showed the advantages of robotic surgery over laparoscopic surgery in intracorporeal reconstruction, total gastrectomy, Ⅰ/Ⅱ stage, and BMI≥25, especially for patients with stage Ⅰ/Ⅱ, there is better overall survival and disease-free survival. CONCLUSION: Our findings point to robotic surgery having great benefits compared with laparoscopic surgery in gastric cancer. Our study may help inform decision-making in applying robotic surgical systems to clinical treatment.

Akkermansia muciniphila ameliorates colonic injury in mice with DSS-induced acute colitis by blocking macrophage pro-inflammatory phenotype switching via the HDAC5/DAB2 axis.

Akkermansia muciniphila (A. muciniphila), a probiotic, has been linked to macrophage phenotypic polarization in different diseases. However, the role and mechanisms of A. muciniphila in regulating macrophage during ulcerative colitis (UC) are not clear. This research aimed to examine the impact of A. muciniphila on dextran sulfate sodium (DSS)-induced acute colitis and elucidate the underlying mechanism related to macrophage phenotypic polarization. A. muciniphila inhibited weight loss, increased disease activity index, and ameliorated inflammatory injury in colonic tissues in mice induced with DSS. Furthermore, A. muciniphila reduced macrophage M1 polarization and ameliorated epithelial barrier damage in colonic tissues of DSS-induced mice through inhibition of histone deacetylase 5 (HDAC5). In contrast, the effect of A. muciniphila was compromised by HDAC5 overexpression. HDAC5 deacetylated H3K9ac modification of the disabled homolog 2 (DAB2) promoter, which led to repressed DAB2 expression. DAB2 overexpression blocked HDAC5-induced pro-inflammatory polarization of macrophages, whereas knockdown of DAB2 resulted in the loss of effects of A. muciniphila against colonic injury in DSS-induced mice. Taken together, A. muciniphila-induced loss of HDAC5 hampered the deacetylation of DAB2 and enhanced the expression of DAB2. Our findings propose that A. muciniphila may be a possible probiotic agent for alleviating DSS-induced acute colitis.