Comparison of intravesical chemotherapy regimens after radical nephroureterectomy for upper tract urothelial carcinoma and analysis of risk factors for postoperative recurrence.

OBJECTIVE: Upper tract urothelial carcinoma (UTUC) is a relatively rare but aggressive type of urologic cancer that includes renal pelvic tumors and ureteral tumors with a poor prognosis. Full-length nephroureterectomy plus sleeve bladder resection is the standard treatment for the disease, but patients are prone to recurrence of bladder tumors after surgery. Intravesical infusion therapy is the main means to prevent the recurrence and progression of bladder cancer. Epirubicin and gemcitabine are widely used in clinical practice as first-line or salvage therapy for intravesical chemotherapy; however, the efficacy of these agents is rarely discussed. The purpose of this study was to investigate the effects of epirubicin and gemcitabine on the occurrence of bladder cancer after radical nephroureterectomy for UTUC and to analyze the risk factors affecting the recurrence of postoperative bladder cancer. PATIENTS AND METHODS: A total of 215 patients with diagnosed UTUC and treated in our hospital from June 2019 to August 2021 were retrospectively selected as the research subjects, and they were divided into an observation group (120 cases) and a control group (95 cases) according to different treatment methods. The patients in the control group were treated with epirubicin, while those in the observation group received gemcitabine. All patients were followed up by telephone or outpatient examination for 12 months to record the occurrence of adverse reactions. The occurrence of bladder cancer was recorded at 3 months, 6 months, and 12 months after the surgery. According to the occurrence of bladder cancer after surgery, the patients were divided into a bladder cancer group (63 cases) and a non-bladder cancer group (152 cases). Multivariate Logistic regression analysis was used to analyze the risk factors of bladder cancer after surgery. RESULTS: The total incidence of adverse reactions in the control group was 49.47%, which was higher than that in the observation group with 15.00% (p<0.01). The incidence of bladder tumors in the observation group and the control group was 0.00% and 2.11% at 3 months, 5.00% and 8.42% at 6 months, 13.33% and 15.79% at 12 months, without significant difference (p>0.05). After 12 months of perfusion, the levels of acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in the two groups were significantly lower than those before perfusion (p<0.05). In the observation group, the levels of these three factors were slightly decreased compared with those in the control group, without a significant difference (p>0.05). Between the bladder cancer and non-bladder cancer groups, there were significant differences in tumor location, number of lesions, tumor stage, preoperative ureteral examination, and preoperative history of bladder cancer (p<0.05). The above indexes were all risk factors for postoperative bladder cancer (p<0.05). CONCLUSIONS: Epirubicin and gemcitabine reduced the occurrence of bladder cancer and effectively inhibited tumor angiogenesis after radical nephroureterectomy for UTUC. The tumor location, number of lesions, tumor stage, preoperative ureteral examination, and preoperative history of bladder cancer were risk factors for postoperative bladder cancer.

Understanding the influence of surgical parameters on craniofacial surgery outcomes: a computational study.

Sagittal craniosynostosis (SC) is a congenital condition whereby the newborn skull develops abnormally owing to the premature ossification of the sagittal suture. Spring-assisted cranioplasty (SAC) is a minimally invasive surgical technique to treat SC, where metallic distractors are used to reshape the newborn's head. Although safe and effective, SAC outcomes remain uncertain owing to the limited understanding of skull-distractor interaction and the limited information provided by the analysis of single surgical cases. In this work, an SC population-averaged skull model was created and used to simulate spring insertion by means of the finite-element analysis using a previously developed modelling framework. Surgical parameters were varied to assess the effect of osteotomy and spring positioning, as well as distractor combinations, on the final skull dimensions. Simulation trends were compared with retrospective measurements from clinical imaging (X-ray and three-dimensional photogrammetry scans). It was found that the on-table post-implantation head shape change is more sensitive to spring stiffness than to the other surgical parameters. However, the overall end-of-treatment head shape is more sensitive to spring positioning and osteotomy size parameters. The results of this work suggest that SAC surgical planning should be performed in view of long-term results, rather than immediate on-table reshaping outcomes.

New sights in ectopic varices in portal hypertension.

Ectopic varices and associated bleeding, although rare, pose a significant risk to patients with portal hypertension, carrying a relatively high mortality rate. These varices can occur in various anatomical regions, excluding the gastroesophageal region, which is typically associated with portal vein drainage. The limited data available in the literature, derived mostly from case reports and series, make the diagnosis and treatment of ectopic variceal bleeding particularly challenging. Furthermore, it is crucial to recognize that ectopic varices in different sites can exhibit variations in key decision-making factors such as aetiology and vascular anatomy, severity and bleeding risk and hepatic reserve. These factors significantly influence treatment strategies and underscore the importance of adopting individualized management approaches. Therefore, the objective of this review is to provide a comprehensive overview of the fundamental knowledge surrounding ectopic varices and to propose site-oriented, stepwise diagnosis and treatment algorithms for this complex clinical issue. A multidisciplinary treatment approach is strongly recommended in managing ectopic varices. In addition, to enhance clinical reference, we have included typical case reports of ectopic varices in various sites in our review, while being mindful of potential publication bias.

Magnetic resonance imaging assessment of substantia nigral iron deposition in Parkinson's disease: a meta-analysis.

OBJECTIVE: The pathogenesis of Parkinson's disease (PD) is associated with abnormal iron accumulation. Magnetic resonance imaging (MRI) studies have shown that patients with Parkinson's disease have an increased amount of iron in their substantia nigra (SN). We have undertaken a meta-analysis of studies using MRI in PD, to explore the potential role of MRI in diagnosing PD using abnormal iron deposition in SN as a candidate biomarker. MATERIALS AND METHODS: Searches of PubMed, Embase, and Medline databases revealed 16 studies that compared PD patients and healthy controls (HC). A sensitivity analysis and subgroup analysis were performed to evaluate the reliability of our results. Estimates were pooled by the fixed-effects model. As an expression of I2, we computed the proportion of variation due to heterogeneity. RESULTS: We included 16 studies with sample sizes of 435 PD and 355 HC in our meta-analysis. Results showed that SN iron deposition was significantly elevated (p<0.00001) in patients with PD compared to HC ones (SMD=0.72, 95% confidence interval 0.57 to 0.87, p<0.00001). CONCLUSIONS: Our findings, based on a homogeneous group-level analysis, suggest that MRI-based SN iron deposition could be used to distinguish PD from HC. For a more rigorous investigation of SN iron deposition in PD, larger cohort studies are needed.

[Research progress and prospects of artificial intelligence in diagnosis and treatment of colorectal cancer].

Colorectal cancer is one of the most common malignant tumors worldwide. Due to the heterogeneity in patient outcomes and treatment responses to standard therapy regimens, personalized diagnostic and therapeutic strategies have remained a focus of sustained interest in research. In recent years, with the rapid progression of artificial intelligence (AI) technology in the medical field, an abundance of phased research results has emerged in the decision-making for preoperative, intraoperative, and postoperative diagnostic and therapeutic plans for colorectal cancer, demonstrating great potential for application. This new and efficient solution provides for the personalized evaluations and auxiliary diagnoses and treatments of patients with colorectal cancer. In the future, AI systems may continue to advance towards multimodal, multi-omics, and real-time directions. This paper aims to explore the current state of research on the multi-faceted auxiliary applications of AI in the diagnosis and treatment of colorectal cancer, as well as to present a prospective view of the innovations that AI technology could bring to personalized colorectal cancer treatment in the future and the challenges it may face.

Effect of Sc contents on the mechanical properties and damping capacity of Al-Zn-Mg-Cu-Zr-Sc alloys with different grain structures.

Al-Zn-Mg-Cu-Zr-Sc alloys with different Sc contents were fabricated by casting, deformation, and T6 treatment. Deformation methods including rolling and friction-stir processing (FSP) were used to design their grain structure. A low additive amount (0.1) of Sc cannot refine the grains of the alloy with rolling and T6 treatment, and it instead coarsened the grains. The reason was the non-uniform distribution of nanosize Al3(Sc,Zr) phases that led to the occurrence of abnormal grain growth during homogenization. Meanwhile, the alloy with only 0.1Sc exhibited finer grains after FSP and T6 treatment than the alloys subjected to the same process but with higher Sc additive amount. Alloys with rolling-induced elongated grain structure exhibited better mechanical properties, and alloys with FSP-induced fine equiaxed grain structure exhibited higher high-strain and high-temperature internal friction values. These features are important performance parameters for applications in fields where vibration and noise are sensitive. The optimum additive amounts of Sc for alloys with elongated and fine equiaxed grain structures were 0.25 and 0.1, respectively.

SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. PATIENTS AND METHODS: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. RESULTS: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. CONCLUSIONS: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.

Towards identifying a learning curve for robotic abdominal wall reconstruction: a cumulative sum analysis.

INTRODUCTION: Over the past decade, an increase has been seen in robotics used for hernia repair, specifically robotic abdominal wall reconstruction (rAWR). However, the learning curve for rAWR can be steep and presently, little is understood regarding the optimal case volume required to achieve proficiency. The aim of our study was to review skill acquisition and describe the learning curve for rAWR. METHODS: A retrospective, single-surgeon case series of consecutive patients who underwent rAWR from 2018 to 2022. The primary outcome was operative time, obtained from console time identified through the MyIntutive application. A one-sided cumulative sum analysis (CUSUM) curve for the total operative time was derived based on the mean operative time of chronological procedures (207 min). RESULTS: 185 patients underwent rAWR between 2018 and 2022. These patients were more likely to be female, Caucasian, and have undergone two previous hernia repairs. ASA complexity increased over time with ASA 3 being predominant from 2020 onwards. The median hernia length was 15.0 cm and the median width was 7 cm. Average operative time was 207.8 min and decreased over time. The CUSUM analysis identified four phases of skill acquisition with the following case volumes: Initial Learning Curve (0-20), Stabilization Phase (21-55), Second Learning Curve (56-70), 4) Skill Proficiency (> 70). CONCLUSION: In the early learning curve of rAWR, operative time decreased consistently after 70 cases, with an initial inflection after 20 cases. We identified varying stages of skill acquisition that are likely typical of a surgeon as they would progress through the learning curve of advanced robotic surgery. Future studies are needed to confirm the optimal case volume for determining the skill level for the performance of rAWR.

Hydrogen sulfide alleviates lipopolysaccharide-induced myocardial injury through TLR4-NLRP3 pathway.

To investigate the effect of hydrogen sulfide (H2S) on myocardial injury in sepsis-induced myocardial dysfunction (SIMD), male C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg, i.p.) to induce cardiac dysfunction without or with the H2S donor sodium hydrosulfide (NaHS) (50 µmol/kg, i.p.) administration 3 h after LPS injection. Six hours after the LPS injection, echocardiography, cardiac hematoxylin and eosin (HE) staining, myocardial damage and inflammatory biomarkers and Western blot results were analyzed. In mice, the administration of LPS decreased left ventricular ejection fraction (LVEF) by 30 % along with lowered H2S levels (35 % reduction). It was observed that cardiac troponin I (cTnI), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) levels were all increased (by 0.22-fold, 2000-fold and 0.66-fold respectively). HE staining revealed structural damage and inflammatory cell infiltration in the myocardial tissue after LPS administration. Moreover, after 6 h of LPS treatment, toll-like receptor 4 (TLR4) and nod-like receptor protein 3 (NLRP3) expressions were up-regulated 2.7-fold and 1.6-fold respectively. When compared to the septic mice, NaHS enhanced ventricular function (by 0.19-fold), decreased cTnI, TNF-alpha, and IL-1beta levels (by 11 %, 33 %, and 16 % respectively) and downregulated TLR4 and NLRP3 expressions (by 64 % and 31 % respectively). Furthermore, NaHS did not further improve cardiac function and inflammation in TLR4-/- mice or mice in which NLRP3 activation was inhibited by MCC950, after LPS injection. In conclusion, these findings imply that decreased endogenous H2S promotes the progression of SIMD, whereas exogenous H2S alleviates SIMD by inhibiting inflammation via the TLR4-NLRP3 pathway suppression.

Visualization of Chiral Electronic Structure and Anomalous Optical Response in a Material with Chiral Charge Density Waves.

Chiral materials have attracted significant research interests as they exhibit intriguing physical properties, such as chiral optical response, spin-momentum locking, and chiral induced spin selectivity. Recently, layered transition metal dichalcogenide 1T-TaS_{2} has been found to host a chiral charge density wave (CDW) order. Nevertheless, the physical consequences of the chiral order, for example, in electronic structures and the optical properties, are yet to be explored. Here, we report the spectroscopic visualization of an emergent chiral electronic band structure in the CDW phase, characterized by windmill-shaped Fermi surfaces. We uncover a remarkable chirality-dependent circularly polarized Raman response due to the salient in-plane chiral symmetry of CDW, although the ordinary circular dichroism vanishes. Chiral Fermi surfaces and anomalous Raman responses coincide with the CDW transition, proving their lattice origin. Our Letter paves a path to manipulate the chiral electronic and optical properties in two-dimensional materials and explore applications in polarization optics and spintronics.

Coherent Picture on the Pure Spin Transport between Ag/Bi and Ferromagnets.

In a joint effort of both experiments and first-principles calculations, we resolve a hotly debated controversy and provide a coherent picture on the pure spin transport between Ag/Bi and ferromagnets. We demonstrate a strong inverse Rashba-Edelstein effect (IREE) at the interface in between Ag/Bi with a ferromagnetic metal (FM) but not with a ferromagnetic insulator. This is in sharp contrast to the previously claimed IREE at Ag/Bi interface or inverse spin Hall effect dominated spin transport. A more than one order of magnitude modulation of IREE signal is realized for different Ag/Bi-FM interfaces, casting strong tunability and a new direction for searching efficient spintronics materials.

Relationship of resting heart rate and blood pressure with all-cause and cardiovascular disease mortality.

OBJECTIVES: This study aimed to investigate associations of resting heart rate (RHR) and blood pressure (BP) with all-cause and cardiovascular disease (CVD) mortality. STUDY DESIGN: A retrospective cohort study. METHODS: A total of 67,028 Chinese participants aged ≥60 years were included in the analysis. RHR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were evaluated according to quartiles ([41-69, 70-74, 75-79, 80-127 beats/min], [80-119, 120-129, 130-139, 140-238 mm Hg], and [40-70, 71-79, 80-84, 85-133 mm Hg]). Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and CVD mortality with RHR, SBP, and DBP. Restricted cubic splines were used to evaluate the dose-response association. RESULTS: During the 361,975 person-year follow-up, 9326 deaths were recorded, of which 5039 deaths were due to CVD. The risk of all-cause mortality was increased by 25% with the quartiles four vs quartile one of RHR (HR [95% CI]:1.25 [1.17-1.33]), and CVD mortality was increased by 32% (HR [95% CI]: 1.32 [1.22-1.44]). Similar results were observed when comparing the quartiles four vs quartile one of SBP with the risk of all-cause and CVD mortality (HRs [95% CIs]: 1.14 [1.07, 1.22] and 1.23 [1.12. 1.34]) and DBP with the risk of all-cause and CVD mortality (HRs [95% CIs]: 1.17 [1.11. 1.24] and 1.36 [1.26. 1.47]). We found linear associations of RHR, SBP, and DBP with all-cause and CVD mortality (Pnon-linearity >0.05), except for the approximately J-shaped association between DBP and all-cause mortality (Pnon-linearity = 0.008). There was a significant interaction of RHR and SBP with all-cause and CVD mortality (Pinteraction <0.05). CONCLUSIONS: RHR and BP increased the risk of all-cause and CVD mortality, especially fast RHR combined with high SBP.

[Research progress on the effects of the interactions between phage and periodontal pathogens on periodontal disease].

Periodontal disease is among the most prevalent oral diseases. As viruses that may infect bacteria, bacteriophages constitute an important component of the oral microbiome. With the advances in bioinformatics and genomics, the relationships among the bacteriophages, oral microbiome and periodontal disease is gradually being elucidated. As a result, phage therapy has become an emerging approach in the fight against super bacteria and has flourished in recent years. This review article discusses the mechanisms involved in the microbial interactions associated with oral phages and periodontal disease, the role of phages in maintaining a normal periodontal environment, the relationship between the imbalance of phages and the occurrence of periodontal disease, and the use of phage in the treatment of periodontal disease in order to provides references for in-depth research on the mechanisms of phage effects on periodontal disease, as well as the further clinical application of phage therapy.

Remote Mesoscopic Signatures of Induced Magnetic Texture in Graphene.

Mesoscopic conductance fluctuations are a ubiquitous signature of phase-coherent transport in small conductors, exhibiting universal character independent of system details. In this Letter, however, we demonstrate a pronounced breakdown of this universality, due to the interplay of local and remote phenomena in transport. Our experiments are performed in a graphene-based interaction-detection geometry, in which an artificial magnetic texture is induced in the graphene layer by covering a portion of it with a micromagnet. When probing conduction at some distance from this region, the strong influence of remote factors is manifested through the appearance of giant conductance fluctuations, with amplitude much larger than e^{2}/h. This violation of one of the fundamental tenets of mesoscopic physics dramatically demonstrates how local considerations can be overwhelmed by remote signatures in phase-coherent conductors.

High expression of ACE2 in the human lung leads to the release of IL6 by suppressing cellular immunity: IL6 plays a key role in COVID-19.

OBJECTIVE: The pathogenesis of coronavirus disease 2019 (COVID-19) remains clear, and no effective treatment exists. SARS-CoV-2 is the virus that causes COVID-19 and uses ACE2 as a cell receptor to invade human cells. Therefore, ACE2 is a key factor to analyze the SARS-CoV-2 infection mechanism. MATERIALS AND METHODS: We included 9,783 sequencing results of different organs, analyzed the effects of different ACE2 expression patterns in organs and immune regulation. RESULTS: We found that ACE2 expression was significantly increased in the lungs and digestive tract. The cellular immunity of individuals with elevated ACE2 expression is activated, whereas humoral immunity is dampened, leading to the release of many inflammatory factors dominated by IL6. Furthermore, by studying the sequencing results of SARS-CoV-2-infected and uninfected cells, IL6 was found to be an indicator of a significant increase in the number of infected cells. However, although patients with high expression of ACE2 will release many inflammatory factors dominated by IL6, cellular immunity in the colorectum is significantly activated. This effect may explain why individuals with SARS-CoV-2 infection have severe lung symptoms and digestion issues, which are important causes of milder symptoms. CONCLUSIONS: This finding indicates that ACE2 and IL6 inhibitors have important value in COVID-19.

[Genes associated with Wolbachia-induced cytoplasmic incompatibility in natural populations of Culex pipiens pallens: a preliminary study].

OBJECTIVE: To investigate the genes involved in Wolbachia-induced cytoplasmic incompatibility among three natural populations of Culex pipiens pallens in eastern China, so as to provide insights into the development of preventive and control measures for mosquito-borne diseases based on Wolbachia. METHODS: The cytoplasmic incompatibility was tested among three natural populations of C. pipiens pallens collected from Nanjing and Wuxi of Jiangsu Province and Tangkou of Shandong Province using reciprocal crosses. Wolbachia infection was detected in C. pipiens pallens using a PCR assay, and the expression of Wolbachia wsp and WD0513 genes was quantified using a fluorescent quantitative real-time PCR (qPCR) assay. RESULTS: Bidirectional compatibility was found between the natural populations of C. pipiens pallens collected from Nanjing and Wuxi of Jiangsu Province (t = 0.57 and 0.15, both P values > 0.05), while bidirectional incompatibility was seen between the natural populations of C. pipiens pallens collected from Tangkou of Shandong Province and Wuxi of Jiangsu Province (t = 63.81 and 43.51, both P values < 0.01), and between the natural populations of C. pipiens pallens collected from Nanjing of Jiangsu Province and Tangkou of Shandong Province (t = 39.62 and 43.12, both P values < 0.01). Wolbachia wsp gene was amplified in all three natural populations of C. pipiens pallens, and qPCR assay detected no significant difference in the Wolbachia wsp gene expression among the three natural populations of C. pipiens pallens (F = 2.15, P > 0.05). In addition, there was no significant difference in the WD0513 gene expression between the natural populations of C. pipiens pallens collected from Tangkou of Shandong Province and Nanjing of Jiangsu Province (q = 8.42, P < 0.05) or between the natural populations of C. pipiens pallens collected from Tangkou of Shandong Province and Wuxi of Jiangsu Province (q = 7.84, P < 0.05); however, there was a significant difference detected in the WD0513 gene expression between the natural populations of C. pipiens pallens collected from Nanjing and Wuxi of Jiangsu Province (q = 0.40, P > 0.05). CONCLUSIONS: Different Wolbachia numbers are detected in natural populations of C. pipiens pallens collected from Nanjing and Wuxi of Jiangsu Province and Tangkou of Shandong Province, and WD0513 gene may be involved in the Wolbachia-induced cytoplasmic incompatibility among three natural populations of C. pipiens pallens.

Metallic elements and Pb isotopes in PM2.5 in three Chinese typical megacities: spatial distribution and source apportionment.

Heavy metal pollution in fine particulate matter (PM2.5) is a serious environmental and health concern in China, particularly during winter. Here, we detected 40 elements in 24 h integrated daily PM2.5 samples collected in January 2014 from three typical Chinese metropolises (Beijing, Changchun, and Chengdu) to reflect elemental spatial variations, local sources, and regional transport. The measured elemental concentrations in Changchun were 11.1% and 48.4% higher than those in Beijing and Chengdu, respectively. Thus, PM2.5 from Changchun exhibited high levels and diversity in the elemental profile (characterized by high concentrations of industrial emission elemental markers). The results of elemental ratios and Pb isotopes proved that, except for a coal combustion source, vehicular emissions contributed more to PM2.5 heavy metals in Beijing than in the other two cities; Changchun PM2.5 elements received large contributions from industrial sources, including iron and steel manufacturing, and automobile industry. Moreover, crustal dust from long-range transport of regional air masses from the northwest regions of China played a crucial role in determining elemental levels in Beijing and Changchun, accounting for more than 50% of source intensity. However, a specific dominant source was not determined in Chengdu; the contribution of anthropogenic dust, mainly from construction activities, needs to be paid attention in Chengdu eastern area. This study contributed to enhancing our understanding of elemental spatial distribution characteristics and sources and to setting more judicious standards and strategies for PM2.5 bound heavy metals in China.

[Complexity of Detecting CRISPR/Cas9-Mediated Homologous Recombination in Zebrafish].

Homology-directed (HD) genome modification offers an opportunity to precisely modify the genome. Despite reported successful cases, for many loci, precise genome editing remains challenging and inefficient in vivo. Here we report an effort to precisely knock-in a GFP reporter into gad locus mediated by CRISPR/Cas9 system in the zebrafish Danio rerio. PCR artifact was detected in testing for homologous recombination (HR), but was mitigated by optimizing PCR condition and decreasing the injected targeting plasmid concentration. Under this optimized condition, time course analysis revealed a decline of the HR-positive embryos at embryogenesis progressed. GFP signals also diminished at later developmental stages. The GFP signals were consistent with PCR detection, both of which suggested the loss of targeted insertion events at later stages. Such loss of insertion might be one underlying reason for the inability to obtain germ-line transgenic lines with GFP knocked into the gad locus. Our results suggest that the low HR efficiency associated with CRISPR-mediated knock-in is in part due to loss of insertion after targeted integration into the gad locus.

Dual Targeting of CDK4/6 and BCL2 Pathways Augments Tumor Response in Estrogen Receptor-Positive Breast Cancer.

PURPOSE: Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor-positive (ER+) breast cancer, relapse is almost inevitable. This may, in part, reflect the failure of CDK4/6 inhibitors to induce apoptotic cell death. We therefore evaluated combination therapy with ABT-199 (venetoclax), a potent and selective BCL2 inhibitor. EXPERIMENTAL DESIGN: BCL2 family member expression was assessed following treatment with endocrine therapy and the CDK4/6 inhibitor palbociclib. Functional assays were used to determine the impact of adding ABT-199 to fulvestrant and palbociclib in ER+ breast cancer cell lines, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. A syngeneic ER+ mouse mammary tumor model was used to study the effect of combination therapy on the immune system. RESULTS: Triple therapy was well tolerated and produced a superior and more durable tumor response compared with single or doublet therapy. This was associated with marked apoptosis, including of senescent cells, indicative of senolysis. Unexpectedly, ABT-199 resulted in Rb dephosphorylation and reduced G1-S cyclins, most notably at high doses, thereby intensifying the fulvestrant/palbociclib-induced cell-cycle arrest. Interestingly, a CRISPR/Cas9 screen suggested that ABT-199 could mitigate loss of Rb (and potentially other mechanisms of acquired resistance) to palbociclib. ABT-199 did not abrogate the favorable immunomodulatory effects of palbociclib in a syngeneic ER+ mammary tumor model and extended tumor response when combined with anti-PD1 therapy. CONCLUSIONS: This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ER+ breast cancer.

Antibacterial Effects of Schisandra chinensis Extract on Escherichia coli and its Applications in Cosmetic.

Schisandra chinensis (Turcz.) Baill (S. chinensis), an edible traditional medicine herb, has a strong constitution, which extract has good antibacterial activity. The study investigated its antibacterial properties on E. coli, to find a candidate for the development as new preservative. In vitro antibacterial assay showed that S. chinensis extract (SCE) effectively inhibited the growth of test bacteria with MBC of 18 mg/mL. In model cosmetic system of O/W emulsions, SCE possessed a great antibacterial capacity. The growth curves of E. coli treated with SCE exhibited an extended lag phase and restricted log phase. Scanning electron microscopy showed that the treated E. coli cells exhibited wrinkled and withered surfaces, and disappearing outmost layer, suggesting S. chinensis extract can damage S. aureus cell member and wall, in addition, the leakage of periplasm enzyme AKPase and the increased activities of Na+/K+-ATPase and Ca++-ATPase in cell membrane were also consistent with the microscopy results. Moreover, the S. chinensis extract can decrease the activities of dehydrogenase and total ATPase and the content of intracellular proteins, and bind with S. aureus DNA by electrostatic and groove binding. The results indicated that SCE might be a candidate cosmetic preservative for its good antibacterial activity and multiple targets on E. coli.