Accessing 1,8-Naphthyridone-3-carboxylic Acid Derivatives and Application to the Synthesis of Amfonelic Acid.

1,8-Naphthyridone-3-carboxyl is the core structure of several on-market antibacterial drugs. It has prompted significant interest from the synthetic community. Here, we report a practical synthesis of diversely functionalized 1,8-naphthyridone-3-carboxylic acid derivatives starting from readily available and inexpensive nicotinic acid derivatives. All key steps have been optimized. Furthermore, the usefulness of this protocol has been exemplified by the first synthesis of amfonelic acid.

Assessment of aortic dilatation in Chinese children and adolescents with Turner syndrome: a single center experience.

BACKGROUND: Patients with Turner syndrome (TS) face an increased risk of developing aortic dilatation (AD), but diagnosing AD in children presents greater complexity compared to adults. This study aimed to investigate the application of various assessment indicators of AD in Chinese children and adolescents with TS. METHODS: This study included TS patients admitted to Shenzhen Children's Hospital from 2017 to 2022. Cardiovascular lesions were diagnosed by experienced radiologists. Patients without structural heart disease were divided into different body surface area groups, then the Chinese TS population Z-score (CHTSZ-score) of the ascending aorta was calculated and compared with other indicators such as aortic size index (ASI), ratio of the ascending to descending aortic diameter (A/D ratio), and TSZ-score (Quezada's method). RESULTS: A total of 115 TS patients were included, with an average age of 10.0 ± 3.7 years. The incidences of the three most serious cardiovascular complications were 9.6% (AD), 10.4% (coarctation of the aorta, CoA), and 7.0% (bicuspid aortic valve, BAV), respectively. The proportion of developing AD in TS patients aged ≥ 10 years was higher than that in those < 10 years old (16.6% vs. 1.8%, P = 0.009), and the proportion of patients with CoA or BAV who additionally exhibited AD was higher than those without these conditions (31.6% vs. 5.2%, P < 0.001). The ASI, A/D ratio, TSZ-score, and CHTSZ-score of the 11 patients with AD were 2.27 ± 0.40 cm/m2, 1.90 ± 0.37, 1.28 ± 1.08, and 3.07 ± 2.20, respectively. Among the AD patients, only 3 cases had a TSZ-score ≥ 2, and 2 cases had a TSZ-score ≥ 1. However, based on the assessment using the CHTSZ-score, 6 patients scored ≥ 2, and 5 patients scored ≥ 1. In contrast, the TSZ-score generally underestimated the aortic Z-scores in Chinese children with TS compared to the CHTSZ-score. CONCLUSIONS: The applicability of ASI and A/D ratio to children with TS is questionable, and racial differences can affect the assessment of TSZ-score in the Chinese population. Therefore, establishing the CHTSZ-score specifically tailored for Chinese children and adolescents is of paramount importance.

Mesenchymal stem cell-derived exosomal miR-548x-3p inhibits pyroptosis of vascular endothelial cells through HMGB1 in heat stroke.

Heat stroke (HS) is an acute physical illness associated with a higher risk of organ dysfunction. This study is the first to explore exosomal miR-548x-3p derived from human bone marrow mesenchymal stem cells (BMSCs) in the pyroptosis of vascular endothelial cells (VECs) associated with HS. Human BMSCs-derived exosome alleviated the injury of the heart, liver, kidney and ileum tissues, the increase of IL-1ß, IL-18 and TNF-α levels, pyroptosis of endothelial cells and the increase of HGMB1, NLRP3, ASC, caspase1 and GSDMD-N protein expression in HS mice and HS-induced human umbilical vein endothelial cells (HUVECs). miR-548x-3p was down-expressed in HS patients, while up-expressed in BMSCs-derived exosome. BMSCs-ExomiR-548x-3p mimics to inhibit pyroptosis, inflammation and HGMB1/NLRP3 activation in HS-induced HUVECs and HS mice, which were blocked by overexpression of HMGB1. In conclusion, human BMSCs-derived exosomes carried miR-548x-3p mimics to inhibit pyroptosis of VECs through HMGB1 in HS mice.

Toward a low carbon path: Do E-commerce reduce CO2 emissions? Evidence from China.

To address global climate change, achieving carbon peak and carbon neutrality has become a global consensus. However, the means to simultaneously achieve carbon reduction and promote green economic development, particularly in developing countries, require further investigation. This study evaluates the impact of e-commerce on CO2 emissions. Through an examination of the effects of the National E-Commerce Demonstration City (NEDC) policy from 2006 to 2017, this paper reveals that e-commerce growth facilitated by the NEDC policy resulted in a 7.89% reduction in total CO2 emissions and a per capita reduction of 1.1146 tons in the pilot cities. Mechanism analysis demonstrates that the upgrading of industrial structure, development of digital finance, and the growth of innovation and entrepreneurship serve as primary pathways for this impact. The robustness of the findings is supported by parallel trend tests, placebo tests, and additional sensitivity analyses. Furthermore, the research reveals that the NEDC policy exhibits a more significant reduction in CO2 emissions in cities with higher levels of economic development and non-resource-based cities. Welfare analyses show that the NEDC policy has significant socio-economic effects. These findings provide new evidence on the environmental effects of the digital economy and offer insights into achieving carbon neutrality.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Broadly neutralizing antibodies recognizing different antigenic epitopes act synergistically against the influenza B virus.

The discovery of broadly neutralizing monoclonal antibodies against influenza viruses has raised hope for the successful development of new antiviral drugs. However, due to the speed and variety of mutations in influenza viruses, single-component antibodies that recognize specific epitopes are susceptible to viral escape and have limited efficacy when administration is delayed. Hence, it is necessary to develop alternative strategies with better antiviral activity. Influenza B virus infection can cause severe illness in children and the elderly. Commonly used anti-influenza drugs have low clinical efficacy against influenza B virus. In this study, we investigated the antiviral efficacy of combinations of representative monoclonal antibodies targeting different antigenic epitopes against the influenza B virus. We found that combinations of antibodies recognizing the hemagglutinin (HA) head and stem regions showed a stronger neutralizing activity than single antibodies and other antibody combinations in vitro. In addition, we found that pair-wise combinations of antibodies recognizing the HA head region, HA stem region, and neuraminidase enzyme-activated region showed superior antiviral activity than single antibodies in both mouse and ferret in vivo protection assays. Notably, these antibody combinations still displayed good antiviral efficacy when treatment was delayed. Mechanistic studies further revealed that combining antibodies recognizing different epitope regions resulted in extremely strong antibody-dependent cell-mediated cytotoxicity, which may partly explain their superior antiviral effects. Together, the findings of this study provide new avenues for the development of better antiviral drugs and vaccines against influenza viruses.

Detoxification and removal of arsenite by Pseudomonas sp. SMS11: Oxidation, biosorption and bioaccumulation.

Arsenite [As(III)] oxidizing bacteria have been widely studied for their detoxification ability through transforming As(III) into arsenate [As(V)]. However, few was focused on removal capacity of arsenic (As). In the current study, As(III) oxidation accompanied with removal of total As was observed in Pseudomonas sp. SMS11. The biosorption (unbinding and surface binding) and bioaccumulation (intracellular uptake) of As by the cells were investigated. Biosorption isotherm was defined adequately by Langmuir and Freundlich models. Biosorption kinetics was recommended by pseudo second-order model. For comparison, the bacteria were inoculated in pure water or culture media amended with different concentrations of As(III) to evaluate the remediation capacity without or with bacterial growth. After removing unbound As, surface bound and intracellular As were sequentially separated using EDTA elution and acidic extraction from bacterial cells. Without bacterial growth, oxidation of As(III) was retarded and the maximum values of surface bound and intracellular As were 4.8 and 10.5 mg/g, respectively. Efficient oxidation and high adsorption capacity were observed after bacterial growth. The surface bound and intracellular As achieved up to 555.0 and 2421.5 mg/g, respectively. Strain SMS11 exhibited great accumulation capacity of As in aqueous solutions, indicating potential application in detoxification and removal of As(III) contamination. The results also suggested that bioremediation via bacteria should be based on living cells and bacterial growth rate.

[Comparison of detection rates of chromosome G-banding karyotype analysis and fluorescence in situ hybridization among children with sex chromosome mosaicisms].

OBJECTIVE: To explore the coincidence rate of G-banding karyotype analysis and fluorescence in situ hybridization (FISH) for the diagnosis of children with sex chromosome mosaicisms. METHODS: A retrospective analysis was carried out for 157 children with suspected sex chromosome abnormalities who had presented at Shenzhen Children's Hospital from April 2021 to May 2022. Interphase sex chromosome FISH and G-banding karyotyping results were collected. The coincidence rate of the two methods in children with sex chromosome mosaicisms was compared. RESULTS: The detection rates of G-banding karyotype analysis and FISH were 26.1% (41/157) and 22.9% (36/157) , respectively (P > 0.05). The results of G-banding karyotype analysis showed that 141 cases (89.8%) were in the sex chromosome homogeneity group, of which only 5 cases (3.5%) were inconsistent with the results of FISH. There were 16 cases (10.2%) in the sex chromosome mosaicism group, of which 11 cases (68.8%) were inconsistent with the results of FISH. There was a statistical difference between the two groups in the coincidence rate of the results of the two methods (P < 0.05). CONCLUSION: No significant difference was found between G-banding karyotype analysis and FISH in the detection rate of chromosome abnormalities. The coincidence rate in the mosaicism group was lower than that in the homogeneity group, and the difference was statistically significant. The two methods should be combined for clinical diagnosis.

Association of the collagen signature with pathological complete response in rectal cancer patients.

Collagen in the tumor microenvironment is recognized as a potential biomarker for predicting treatment response. This study investigated whether the collagen features are associated with pathological complete response (pCR) in locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (nCRT) and develop and validate a prediction model for individualized prediction of pCR. The prediction model was developed in a primary cohort (353 consecutive patients). In total, 142 collagen features were extracted from the multiphoton image of pretreatment biopsy, and the least absolute shrinkage and selection operator (Lasso) regression was applied for feature selection and collagen signature building. A nomogram was developed using multivariable analysis. The performance of the nomogram was assessed with respect to its discrimination, calibration, and clinical utility. An independent cohort (163 consecutive patients) was used to validate the model. The collagen signature comprised four collagen features significantly associated with pCR both in the primary and validation cohorts (p < 0.001). Predictors in the individualized prediction nomogram included the collagen signature and clinicopathological predictors. The nomogram showed good discrimination with area under the ROC curve (AUC) of 0.891 in the primary cohort and good calibration. Application of the nomogram in the validation cohort still gave good discrimination (AUC = 0.908) and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. In conclusion, the collagen signature in the tumor microenvironment of pretreatment biopsy is significantly associated with pCR. The nomogram based on the collagen signature and clinicopathological predictors could be used for individualized prediction of pCR in LARC patients before nCRT.

Murine diabetic models for dengue virus infection.

Dengue virus (DENV) is a critical public health concern in tropical and subtropical regions worldwide. Thus, immunocompetent murine models of DENV infection with robust viremia are required for vaccine studies. Diabetes is highly prevalent worldwide, making it frequent comorbidity in patients with dengue fever. Therefore, murine models are needed to understand viral pathogenesis and disease progression. Acquired-induced and inherently diabetic C57BL/6 and db/db mice were inoculated with DENV-3 via the tail vein. After infection, both the diabetic C57BL/6 and db/db mice showed obvious weight loss with clinical manifestations. Quantitative reverse-transcription polymerase chain reaction revealed robust and replicable viremia in the two types of diabetic mice. Immunohistochemical detection showed persistent DENV-3 infection in the liver. Enzyme-linked immunosorbent assay for cytokine detection revealed that diabetic mice showed more severe inflammatory responses than did nondiabetic mice, and significant histological alterations were observed in diabetic mice. Thus, the diabetic mice were more susceptible to DENV infection than the nondiabetic mice. Taken together, we established two types of immunocompetent diabetic mice for DENV infection, which can be used to further study the mechanisms of dengue pathogenesis in diabetes and to develop antiviral pharmaceuticals and treatments.

Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3ß signaling pathway.

Ginsenoside-Rg1 (G-Rg1), a saponin that is a primary component of ginseng, is effective against inflammatory diseases. The P2X purinoceptor 7 (P2X7) receptor is an ATP-gated ion channel that is predominantly expressed in immune cells and plays a key role in inflammatory processes. We investigated the role of G-Rg1 in sepsis-related cardiac dysfunction and the underlying mechanism involving the regulation of the P2X7 receptor. We detected cell viability, cytotoxicity, cellular reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP) with or without G-Rg1 in lipopolysaccharide (LPS)- or hypoxia/reoxygenation (H/R)-induced H9c2 cell models of ischemia/reperfusion injury. We applied cecal ligation and puncture (CLP) to induce a mouse model of sepsis and measured the survival duration and cardiac function of CLP mice. Next, we quantified the ROS level, MMP, respiratory chain complex I-IV enzymatic activity, and mitochondrial fusion in CLP mouse heart tissues. We then investigated the role of G-Rg1 in repairing LPS-induced cell mitochondrial damage, including mitochondrial superoxidation products. The results showed that G-Rg1 inhibited LPS- or H/R-induced cardiomyocyte apoptosis, cytotoxicity, ROS levels, and mitochondrial damage. In addition, G-Rg1 prolonged the survival time of CLP mice. G-Rg1 attenuated LPS-induced superoxide production in the mitochondria of cardiomyocytes and the excessive release of cytochrome c from mitochondria into the cytoplasm. Most importantly, G-Rg1 suppressed LPS-mediated induction of proapoptotic Bax, activated Akt, induced GSK-3ß phosphorylation, and balanced mitochondrial calcium levels. Overall, G-Rg1 activates the Akt/GSK-3ß pathway through P2X7 receptors to inhibit sepsis-induced cardiac dysfunction and mitochondrial dysfunction.

Spatial-temporal evolution of the allometric growth between economic scale and carbon emissions in China's cities and its driving mechanism.

Exploring the relationship between economic development and carbon emissions is a hot issue of concern to academia. Taking Chinese cities as the research object, this study constructed an allometric growth model of economic scale and carbon emissions to analyze the spatial-temporal evolution of their allometric growth from 2000 to 2017. Additionally, the geographical detector model was used to reveal the driving mechanism of allometric growth. The findings were as follows. (1) The spatial-temporal patterns of economic scale and carbon emissions were dominated by hot spots. Additionally, their size distribution was in an equilibrium stage. (2) The gap between the economic growth rate of Chinese cities and the growth rate of carbon emissions grew, reflecting the remarkable achievements in carbon emission reduction in Chinese cities as a whole. The scaling exponent declined from east to the west during 2000-2008, but showed the opposite trend during 2009-2017. The proportion of cities with negative allometric growth in the sample cities increased from 76.49 to 97.86%. (3) The influence of city investment intensity, energy utilization efficiency, technological development level, social consumption level, fiscal investment level and economic development level on allometric growth gradually decreases. These factors were also the main factors affecting the spatial-temporal heterogeneity of allometric growth. (4) The impact of various factors had a synergetic enhancement effect. These factors can be classified as economic factors, environmental factors and a combination of them. Under the nonlinear coupling of multiple factors, a spatially differentiated pattern of allometric growth was formed.

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Total neoadjuvant therapy (TNT) is a novel approach for locally advanced rectal cancer (LARC), which attempts to deliver both systemic chemotherapy and neoadjuvant chemoradiotherapy prior to surgery. However, its efficacy and safety remain controversial in randomized controlled trials (RCTs). We conducted this meta-analysis to assess such concerns. MATERIALS AND METHODS: Head-to-head phase II/III RCTs were searched in Embase, PubMed, Web of Science, and the Cochrane Library, as well as other sources. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were disease-free survival (DFS), overall survival (OS), local recurrence-free survival, distant metastasis-free survival, and the R0 resection rate. RESULTS: Eight phase II/III RCTs involving 2,196 patients with LARC were assessed. The primary analysis demonstrated a statistically significant improvement in the pCR rate for TNT treatment (odds ratio, 1.77; 95% confidence interval [CI], 1.28-2.45; p = .0005). TNT treatment also showed improvements in DFS and OS outcomes compared with standard chemoradiotherapy (hazard ratio [HR], 0.83; 95% CI, 0.72-0.96; p = .03 and HR, 0.88; 95% CI, 0.74-1.05; p = .15). In addition, TNT treatment showed significant efficacy in reducing the risk of distant metastasis (HR, 0.81; 95% CI, 0.68-0.95; p = .012). CONCLUSION: The overall pCR rate may be improved with TNT compared with standard treatment. The TNT strategy may also improve DFS and OS and reduce the risk of distant metastasis. IMPLICATIONS FOR PRACTICE: Locally advanced rectal cancer (LARC) is a relatively common disease, with a poor prognosis because of its high metastatic potential. The role of total neoadjuvant therapy (TNT) has always been controversial. This meta-analysis found that TNT in LARC is associated with a significant improvement in overall pathologic complete response rate, disease-free survival, overall survival, and distant metastasis-free survival compared with standard treatment. TNT is a promising strategy for LARC, especially for patients who have little desire for surgery.

A Nomogram Based on a Collagen Feature Support Vector Machine for Predicting the Treatment Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer Patients.

BACKGROUND: The relationship between collagen features (CFs) in the tumor microenvironment and the treatment response to neoadjuvant chemoradiotherapy (nCRT) is still unknown. This study aimed to develop and validate a perdition model based on the CFs and clinicopathological characteristics to predict the treatment response to nCRT among locally advanced rectal cancer (LARC) patients. METHODS: In this multicenter, retrospective analysis, 428 patients were included and randomly divided into a training cohort (299 patients) and validation cohort (129 patients) [7:3 ratio]. A total of 11 CFs were extracted from a multiphoton image of pretreatment biopsy, and a support vector machine (SVM) was then used to construct a CFs-SVM classifier. A prediction model was developed and presented with a nomogram using multivariable analysis. Further validation of the nomogram was performed in the validation cohort. RESULTS: The CFs-SVM classifier, which integrated collagen area, straightness, and crosslink density, was significantly associated with treatment response. Predictors contained in the nomogram included the CFs-SVM classifier and clinicopathological characteristics by multivariable analysis. The CFs nomogram demonstrated good discrimination, with area under the receiver operating characteristic curves (AUROCs) of 0.834 in the training cohort and 0.854 in the validation cohort. Decision curve analysis indicated that the CFs nomogram was clinically useful. Moreover, compared with the traditional clinicopathological model, the CFs nomogram showed more powerful discrimination in determining the response to nCRT. CONCLUSIONS: The CFs-SVM classifier based on CFs in the tumor microenvironment is associated with treatment response, and the CFs nomogram integrating the CFs-SVM classifier and clinicopathological characteristics is useful for individualized prediction of the treatment response to nCRT among LARC patients.

Prognostic value of ubiquitin E2 UBE2W and its correlation with tumor-infiltrating immune cells in breast cancer.

BACKGROUND: Ubiquitin-conjugating enzyme E2W (UBE2W) is a protein-coding gene that has an important role in ubiquitination and may be vital in the repair of DNA damage. However, studies on the prognostic value of UBE2W and its correlation with tumor-infiltrating immune cells in multiple cancers have not been addressed. METHODS: We investigated UBE2W expression in the Oncomine database, the Tumor Immune Estimation Resource (TIMER), TNMplot database. Then, the clinical prognostic value of UBE2W was analyzed via online public databases. Meanwhile, we explored the correlation between UBE2W and DNA repair associate genes expression and DNA methyltransferase expression by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). By using the same method, the correlation between UBE2W and tumor-infiltrating immune cells was explored. Genomic Profiles of UBE2W in breast cancer (BRCA) were accessed in cBioPortal (v3.5.0). Functional proteins associated network was analyzed by STRING database (v11.0). RESULTS: UBE2W was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels, DNA methyltransferase, and BRCA1/2 expression in breast cancer. High expression of UBE2W may promote the tumor immunosuppression and metastasis, induce endocrine therapy resistance and deteriorate outcomes of patients with breast cancer. These findings suggest that UBE2W could be a potential biomarker of prognosis and tumor-infiltrating immune cells. Besides, RBX1 may be a new E3 that was regulated by UBE2W. CONCLUSIONS: Ubiquitin E2 UBE2W is a potential prognostic biomarker and is correlated with immune infiltration in BRCA.

Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation in stage IV rectal cancer patients with potentially resectable metastases.

BACKGROUND: The optimal treatment of stage IV rectal cancer remains controversial. The purpose of this study was to assess the treatment outcomes and toxicity of neoadjuvant chemotherapy and radiotherapy followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer patients with potentially resectable metastases. METHODS: Adult patients diagnosed with locally advanced rectal adenocarcinoma with potentially resectable metastases, who received neoadjuvant chemotherapy and radiotherapy from July 2013 and September 2019 at Sun Yat-sen University cancer center, were included. Completion of the whole treatment schedule, pathological response, treatment-related toxicity and survival were evaluated. RESULTS: A total of 228 patients were analyzed with a median follow-up of 33 (range 3.3 to 93.4) months. Eventually, 112 (49.1%) patients finished the whole treatment schedule, of which complete response of all tumor sites and pathological downstaging of the rectal tumor were observed in three (2.7%) and 90 (80.4%) patients. The three-year overall survival (OS) and progression-free survival (PFS) of all patients were 56.6% (50.2 to 63.9%) and 38.6% (95% CI 32.5 to 45.8%), respectively. For patients who finished the treatment schedule, 3-year OS (74.4% vs 39.2%, P < 0.001) and 3-year PFS (45.5% vs 30.5%, P = 0.004) were significantly improved compared those who did not finish the treatment. Grade 3-4 chem-radiotherapy treatment toxicities were observed in 51 (22.4%) of all patients and surgical complications occurred in 22 (9.6%) of 142 patients who underwent surgery, respectively. CONCLUSIONS: Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation and subsequent adjuvant chemotherapy offered chances of long-term survival with tolerable toxicities for selected patients with potentially resectable stage IV rectal cancer, and could be considered as an option in clinical practice.

Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall survival and decrease to multivisceral resection.

BACKGROUND: The management of unresectable locally advanced colon cancer (LACC) remains controversial, as resection is not feasible. The goal of this study was to evaluate the treatment outcomes and toxicity of neoadjuvant chemoradiotherapy (NACRT) followed with surgery and adjuvant chemotherapy in patients with unresectable radically LACC. METHODS: We included patients who were diagnosed at our institution, 2010-2018. The neoadjuvant regimen consisted of radiotherapy and capecitabine/ 5-fluorouracil-based chemotherapy. RESULTS: One hundred patients were identified. The median follow-up time was 32 months. The R0 resection rate, adjusted nonmultivisceral resection rate and bladder preservation rate were 83.0, 43.0 and 83.3%, respectively. The pCR and clinical-downstaging rates were 18, and 81.0%%, respectively. The 3-year PFS and OS rates for all patients were 68.6 and 82.1%, respectively. Seventeen patients developed grade 3-4 myelosuppression, which was the most common adverse event observed after NACRT. Tumor perforation occurred in 3 patients during NACRT. The incidence of grade 3-4 surgery-related complications was 7.0%. Postoperative anastomotic leakage was observed in 3 patients. CONCLUSIONS: NACRT followed by surgery was feasible and safe for selected patients with LACC, and can be used as a conversion treatment to achieve satisfactory downstaging, long-term survival and quality of life, with acceptable toxicities.

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision.

BACKGROUND: The efficacy of the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer in elderly patients has not been established. METHODS: A total of 3096 locally advanced rectal cancer patients who received neoadjuvant chemotherapy, along with neoadjuvant chemoradiotherapy and total mesorectal excision, with or without adjuvant chemotherapy, between January 2010 and December 2018, were studied retrospectively. Patients were divided into elderly (>75 years) and younger (≤75 years) groups, and propensity score matching was used to balance a potentially confounding clinical bias. Overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and local recurrence-free survival rates for the two groups were compared. Hazard ratios (HR) with 95% confidence intervals (CI) for different clinicopathological variables were calculated to determine predictors of 3-year overall survival. RESULTS: Mean follow-up was 39.0 (range, 5-140) months. The overall 3-year overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates were 86.1, 87.6, 80.0, 82.4 and 95.4%, respectively. Only 3-year overall survival rates differed significantly between the elderly (77.2%) and younger (88.9%) groups (P = 0.01). Cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates did not differ significantly between the two groups. Significant negative independent prognostic factors for 3-year overall survival were age >75 years (HR = 2.016, 95% CI 1.157-23.511, P = 0.01) and high pathologic TNM stage (yp stage III, P < 0.001). CONCLUSION: For elderly locally advanced rectal cancer patients who have good health and performance status, the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision can result in disease-related survival rates and oncological outcomes similar to those experienced by younger patients. The decision to use this treatment approach in elderly patients should not be based solely on chronological age.

The effects of Japanese encephalitis virus antibodies on Zika virus infection.

Recently, Zika virus (ZIKV) has become more widespread, thus attracting global attention. The vaccine against Japanese encephalitis virus (JEV) is currently used in China, being included in planned immunisation regimes. Although ZIKV and JEV are closely related mosquito-borne Flaviviruses, and a complex cross-immune response within flaviviruses has been demonstrated, the effect of JEV vaccination on ZIKV infection has not been well described. Thus, this study aimed to explore the impact of different titres of anti-JEV antibodies (Abs) against ZIKV infection using sera from healthy human donors in Guangzhou and anti-JEV rabbit polyclonal antibodies (pAbs) in vitro and vivo. Human anti-JEV Ab titres were tested at decreasing concentrations as the age increased. A neutralising effect on ZIKV infection was observed when anti-JEV Ab titres in human sera or rabbit pAbs were high (the corresponding age was under 30 years). Even though a lower titre in human sera showed no apparent effect, whereas rabbit pAbs had an antibody-dependent enhancement(ADE)effect, we proved an ADE effect in vivo for the first time. This study suggests that individuals over 60 years of age are at high risk for JEV and ZIKV infection, and screening this age group for infection should strengthen. Furthermore, a deep exploration of the relationship between anti-JEV Abs and ZIKV infection is needed.