Whole tumour- and subregion-based radiomics of contrast-enhanced mammography in differentiating HER2 expression status of invasive breast cancers: A double-centre pilot study.

OBJECTIVES: To explore the value of whole tumour- and subregion-based radiomics of contrast-enhanced mammography (CEM) in differentiating the HER2 expression status of breast cancers. METHODS: 352 patients underwent preoperative CEM from two centres were consecutively enroled and divided into the training, internal validation, and external validation cohorts. The lesions were divided into HER2-positive and HER2-negative groups. Besides the radiological features, radiomics features capturing the whole tumour-based (wITH) and subregion-based intratumoral heterogeneity (sITH) were extracted from the craniocaudal view of CEM recombined images. The XGBoost classifier was applied to develop the radiological, sITH, and wITH models. A combined model was constructed by fusing the prediction results of the three models. RESULTS: The mean age of the patients was 51.1 ± 10.7 years. Two radiological features, four wITH features, and three sITH features were selected to establish the models. The combined model significantly improved the AUC to 0.80 ± 0.03 (95% CI: 0.73-0.86), 0.79 ± 0.06 (95% CI: 0.67-0.90), and 0.79 ± 0.05 (95% CI: 0.69-0.89) in the training, internal validation, and external validation cohorts, respectively (All P < 0.05). The combined model showed good agreement between the predicted and observed probabilities and favourable net clinical benefit in the validation cohorts. CONCLUSIONS: Both whole tumour- and subregion-based ITH radiomics features of CEM exhibited potential for differentiating the HER2 expression status. Combining conventional radiological features and ITH features can improve the model's performance.

The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis.

BACKGROUND AND AIMS: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. APPROACH AND RESULTS: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. CONCLUSIONS: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.

Spleen volume is associated with overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with portal hypertension.

BACKGROUND: Portal shunt and immune status related to the spleen are related to the occurrence of hepatic encephalopathy (HE). It is unknown whether spleen volume before transjugular intrahepatic portosystemic shunt (TIPS) is related to postoperative HE. AIM: To investigate the relationship between spleen volume and the occurrence of HE. METHODS: This study included 135 patients with liver cirrhosis who underwent TIPS, and liver and spleen volumes were elevated upon computed tomography imaging. The Kaplan-Meier curve was used to compare the difference in the incidence rate of HE among patients with different spleen volumes. Univariate and multivariate Cox regression analyses were performed to identify the factors affecting overt HE (OHE). Restricted cubic spline was used to examine the shapes of the dose-response association between spleen volumes and OHE risk. RESULTS: The results showed that 37 (27.2%) of 135 patients experienced OHE during a 1-year follow-up period. Compared with preoperative spleen volume (901.30 ± 471.90 cm3), there was a significant decrease in spleen volume after TIPS (697.60 ± 281.0 cm3) in OHE patients. As the severity of OHE increased, the spleen volume significantly decreased (P < 0.05). Compared with patients with a spleen volume ≥ 782.4 cm3, those with a spleen volume < 782.4 cm3 had a higher incidence of HE (P < 0.05). Cox regression analysis showed that spleen volume was an independent risk factor for post-TIPS OHE (hazard ratio = 0.494, P < 0.05). Restricted cubic spline model showed that with an increasing spleen volume, OHE risk showed an initial increase and then decrease (P < 0.05). CONCLUSION: Spleen volume is related to the occurrence of OHE after TIPS. Preoperative spleen volume is an independent risk factor for post-TIPS OHE.

Experimental evolution reveals an effective avenue for d-lactic acid production from glucose-xylose mixtures via enhanced Glk activity and a cAMP-independent CRP mutation.

d-Lactic acid holds significant industrial importance due to its versatility and serves as a crucial component in the synthesis of environmentally friendly and biodegradable thermal-resistant poly-lactic acid. This polymer exhibits promising potential as a substitute for nonbiodegradable, petroleum-based plastics. The production of d-lactic acid from lignocellulosic biomass, a type of biorenewable and nonfood resources, can lower costs and improve product competitiveness. Glucose and xylose are the most abundant sugar monomers in lignocellulosic biomass materials. Despite Escherichia coli possessing native xylose catabolic pathways and transport, their ability to effectively utilize xylose is often hindered in the presence of glucose. Here, the E. coli strain Rec1.0, previously engineered to overcome carbon catabolite repression, was selected as the initial strain for reengineering to produce d-lactic acid. An adaptive evolution approach was employed to achieve highly efficient fermentation of glucose-xylose mixtures. The resulting strain, QJL010, could produce d-lactic acid of 87.5 g/L with a carbon yield of 0.99 mol/mol. Notably, the consumption rates of glucose and xylose reached 0.75 and 0.82 g/gDCW/h, respectively. Further analysis revealed that increased Glk activity, resulting from glk mutations (A142V and R188H), along with their upregulated expression, contributed to an elevated glucose consumption rate. Additionally, a CRP G141D mutation, cAMP-independent, stimulated the expression of the xylR, xylE, and galABC* genes, resulting in an accelerated xylose consumption rate. These findings provide valuable support for the utilization of E. coli platform strains in the production of value-added chemicals from lignocellulosic biomass.

Increased risk of cardiovascular disease among kidney cancer survivors: a nationwide population-based cohort study.

Background: Cardiovascular disease (CVD) is a major concern of morbidity and mortality among cancer survivors. However, few evidence exists on the short- and long-term risk of CVD in kidney cancer (KCa) survivors. Methods: In this nationwide, large population-based retrospective cohort study, we used the Korean national health insurance and medical checkup survey linkage database (2007-2021), drawn from the entire Korean population. We included adults diagnosed with KCa as the first primary cancer and matched them to an individual without KCa at a 1:5 ratio. The primary outcome was CVD incidence, including myocardial infarction, stroke, atrial fibrillation, heart failure, peripheral arterial occlusion, and venous thromboembolism (VTE). We evaluated CVD risk at 6 months, 1 year, and 5 years following cancer diagnosis, using Fine-Gray competing risk models that accounted for death as a competing factor. Results: A total of 149,232 participants were included (KCa survivors: N=20,093 and matched non-KCa individuals: N=129,139). After 6-month follow-up, KCa survivors showed an increased risk of CVD compared to the general population (subdistribution hazard ratio (HR) 2.70, 95% confidence interval (CI) 2.31-3.15). After 1 year, KCa survivors had a higher risk of CVD (HR=1.77, 95% CI: 1.56-2.00). After 5 years, this elevated CVD risk remained (HR=1.10, 95% CI: 1.03-1.18), with VTE identified as the primary contributing disease (HR=3.05, 95% CI:2.59-3.59). Conclusion: KCa survivors had an increased risk of CVD up to 5 years after cancer diagnosis compared to the general population. Our findings emphasize the importance of comprehensive healthcare management for both CVD and KCa throughout cancer survivorship.

Magnetic resonance imaging-based prognostic model for subsequent distant metastasis in patients with ipsilateral breast tumor recurrence following breast-conserving surgery.

Background: Ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS) has been considered a risk factor for distant metastasis (DM). Limited data are available regarding the subsequent outcomes after IBTR. Therefore, this study aimed to determine the clinical course after IBTR and develop a magnetic resonance imaging (MRI)-based predictive model for subsequent DM. Methods: We retrospectively extracted quantitative features from MRI to construct a radiomics cohort, with all eligible patients undergoing preoperative MRI at time of primary tumor and IBTR between 2010 and 2018. Multivariate Cox analysis was performed to identify factors associated with DM. Three models were constructed using different sets of clinicopathological, qualitative, and quantitative MRI features and compared. Additionally, Kaplan-Meier analysis was performed to assess the prognostic value of the optimal model. Results: Among the 183 patients who experienced IBTR, 47 who underwent MRI for both primary and recurrent tumors were enrolled. Multivariate analysis demonstrated that the independent prognostic factors were human epidermal growth factor receptor 2 (HER2) status [hazard ratio (HR) =5.40] and background parenchymal enhancement (BPE) (HR =7.94) (all P values <0.01). Furthermore, four quantitative MRI features of recurrent tumors were selected through the least absolute shrinkage and selection operator (LASSO) method. The combined model exhibited superior performance [concordance index (C-index) 0.77] compared to the clinicoradiological model (C-index 0.71; P=0.006) and radiomics model (C-index 0.70; and P=0.01). Furthermore, the combined model successfully categorized patients into low- and high-risk subgroups with distinct prognoses (P<0.001). Conclusions: The clinicopathological and MRI features of IBTR were associated with secondary events following surgery. Additionally, the MRI-based combined model exhibited the highest predictive efficacy. These findings could be helpful in risk stratification and tailoring follow-up strategies in patients with IBTR.

Ambient air pollution and urological cancer risk: A systematic review and meta-analysis of epidemiological evidence.

Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 µg/m3 increase in PM2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 µg/m3 increase in NO2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM2.5 levels to 5.8 µg/m3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden.

Apalutamide and Goserelin for Androgen Receptor-Positive Salivary Gland Carcinoma: A Phase II Nonrandomized Clinical Trial, YATAGARASU.

PURPOSE: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma. PATIENTS AND METHODS: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded. RESULTS: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain. CONCLUSIONS: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer.

Effect of Swimming at Low Temperature on Uncoupling Protein Gene Expression in Skeletal Muscle of Wistar Rats / Efecto de la Natación a Baja Temperatura sobre la Expresión del Gen de la Proteína de Desacoplamiento en el Músculo Esquelético de Ratas Wistar

SUMMARY: As the economy develops and living standards improve, overweight and obesity are increasingly prevalent. Currently, weight-loss medications are primarily administered orally or intravenously, which can result in poor targeting, low bioavailability, frequent administration, and high toxicity and side effects. The study aimed to address these challenges by preparing polylactic acid- polyethylene glycol staple fibers that carry the browning drug pioglitazone hydrochloride using electrostatic spinning and freeze-cutting techniques. Animal experiments were conducted to test the effectiveness of these fibers. Additionally, the study investigated the expression of uncoupling protein genes in rats exposed to different water temperatures by measuring changes in serum urea nitrogen and mRNA expression levels of skeletal muscle uncoupling protein genes. The physiological and genetic effects of low-temperature swimming exercise on changes in energy metabolism in rats were also analyzed at both the individual and molecular levels. The results revealed that serum urea nitrogen remained more stable in hypothermic swimming rats compared to rats in the swimming group. Furthermore, the study observed an induced up-regulation of uncoupling proteins in the skeletal muscle of Wistar rats in response to external temperature stimulation, and the expression of mRNA for skeletal muscle uncoupling proteins significantly increased as the temperature decreased. And the prepared short nanofibers also had a significant promotive effect on uncoupling protein gene, COX7A1, while suppressing the expression of lipogenic gene.

A medida que la economía se desarrolla y los niveles de vida mejoran, el sobrepeso y la obesidad son cada vez más frecuentes. Actualmente, los medicamentos para bajar de peso se administran principalmente por vía oral o intravenosa, lo que puede resultar en una mala focalización, baja biodisponibilidad, administración frecuente y alta toxicidad y efectos secundarios. El estudio tuvo como objetivo abordar estos desafíos mediante la preparación de fibras cortadas de ácido poliláctico y polietilenglicol que transportan el fármaco pardo clorhidrato de pioglitazona mediante técnicas de hilado electrostático y liofilización. Se realizaron experimentos con animales para probar la eficacia de estas fibras. Además, el estudio investigó la expresión de genes de proteínas desacopladoras en ratas expuestas a diferentes temperaturas del agua midiendo los cambios en el nitrógeno ureico sérico y los niveles de expresión de ARNm de genes de proteínas desacopladoras del músculo esquelético. También se analizaron los efectos fisiológicos y genéticos del ejercicio de natación a baja temperatura sobre los cambios en el metabolismo energético en ratas, tanto a nivel individual como molecular. Los resultados revelaron que el nitrógeno ureico sérico permaneció más estable en ratas nadadoras hipotérmicas en comparación con las ratas del grupo de natación. Además, el estudio observó una regulación positiva inducida de las proteínas desacopladoras en el músculo esquelético de ratas Wistar en respuesta a la estimulación de la temperatura externa, y la expresión de ARNm para las proteínas desacopladoras del músculo esquelético aumentó significativamente a medida que disminuía la temperatura. Además, las nanofibras cortas preparadas también tuvieron un efecto promotor significativo sobre el gen de la proteína de desacoplamiento, COX7A1, al tiempo que suprimieron la expresión del gen lipogénico.

Laser-activable murine ferritin nanocage for chemo-photothermal therapy of colorectal cancer.

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.

Hybrid Sequencing-Based Genomic Analysis of Klebsiella pneumoniae from Urinary Tract Infections Among Inpatients at a Tertiary Hospital in Beijing.

Background: Urinary tract infection (UTI) associated with Klebsiella pneumoniae poses a serious threat for inpatients. This study aimed to describe the genomic characteristics of K. pneumoniae causing UTI in a tertiary-care hospital in Beijing, China. Methods: A total of 20 K. pneumoniae strains collected from 2020 to 2021 were performed whole-genome sequencing. The Antibiotic susceptibility of 19 common antimicrobial agents was tested against all strains. The multi-locus sequence types (MLSTs) and serotypes were determined from the WGS data. De novo assemblies were used to identify resistance and virulence genes. The presence and characteristics of the plasmids were detected using hybrid assembly of long and short-read data. Results: These K. pneumoniae strains were clustered into nine sequence types (STs) and twelve K-serotypes. All the carbapenem-resistant K. pneumoniae (CRKP) strains acquired carbapenemase blaKPC-2 (n=7). Two CRKP strains exhibited increased resistance to Polymyxin B with MIC ≥ 4 mg/L due to insertion of an IS5-like sequence in the mgrB gene, and they were also involved in a transmission event in Intensive Care Unit. Long-read assemblies identified many plasmids co-carrying multiple replicons. Acquisition of a new IncM2_1 type blaCTX-M-3 positive plasmid was observed after transfer from ICU to neurovascular surgery by comparing the two strains collected from the same patient. Conclusion: K. pneumoniae is a significant pathogen responsible for urinary tract infections. The ST11-KL47 strain, prevalent at our hospital, exhibits a combination of high drug resistance and hypervirulence. It is imperative to enhance ongoing genomic surveillance of urinary tract infection-causing pathogens.

Dysphagia Pattern in Early to Moderate Parkinson's Disease Caused by Abnormal Pharyngeal Kinematic Function.

Airway invasion is common in patients with Parkinson's disease (PD) and can cause serious complications. However, a PD-related dysphagic pattern has not been clearly elucidated. In this study, 53 patients with early to moderate PD were enrolled to undergo a videofluoroscopic study of swallowing evaluation (VFSS) and a battery of neuropsychological assessments. A set of VFSS variables (three visuoperceptual, nine temporal, and six spatial) were measured. The main effects of bolus viscosity and volume on airway invasion were calculated. Statistical analyses were performed to determine key kinematic factors of airway invasion for swallowing each bolus type. Airway invasion frequency was significantly higher for liquid boluses (liquid vs. pudding P < 0.001; liquid vs. honey P = 0.006). Laryngeal vestibule closure reaction time (LVCrt) was the key kinematic factor of airway invasion for 3 ml liquid swallow (P = 0.040), anterior displacement of hyoid bone was the key kinematic factor for both 5 ml and 10 ml liquid swallows (P = 0.010, 0.034, respectively). Male sex and advanced Hoehn and Yahr stage were significantly related to reduced anterior displacement of hyoid bone. These results reveal the dysphagic pattern related to PD, demonstrating that prolonged LVCrt and reduced anterior displacement of hyoid bone are two crucial kinematic factors contributing to airway invasion during the liquid swallow. In addition, hyoid bone dysfunction was correlated with disease severity and male sex. Our findings warrant further investigation of the pathophysiological mechanism of dysphagia in PD and would guide clinical intervention.

RNA base editing therapy cures hearing loss induced by OTOF gene mutation.

Otoferlin (OTOF) gene mutations represent the primary cause of hearing impairment and deafness in auditory neuropathy. The c.2485C>T (p. Q829X) mutation variant is responsible for approximately 3% of recessive prelingual deafness cases within the Spanish population. Previous studies have used two recombinant AAV vectors to overexpress OTOF, albeit with limited efficacy. In this study, we introduce an enhanced mini-dCas13X RNA base editor (emxABE) delivered via an AAV9 variant, achieving nearly 100% transfection efficiency in inner hair cells. This approach is aimed at treating OTOFQ829X, resulting in an approximately 80% adenosine-to-inosine conversion efficiency in humanized OtofQ829X/Q829X mice. Following a single scala media injection of emxABE targeting OTOFQ829X (emxABE-T) administered during the postnatal day 0-3 period in OtofQ829X/Q829X mice, we observed OTOF expression restoration in nearly 100% of inner hair cells. Moreover, auditory function was significantly improved, reaching similar levels as in wild-type mice. This enhancement persisted for at least 7 months. We also investigated P5-P7 and P30 OtofQ829X/Q829X mice, achieving auditory function restoration through round window injection of emxABE-T. These findings not only highlight an effective therapeutic strategy for potentially addressing OTOFQ829X-induced hearing loss but also underscore emxABE as a versatile toolkit for treating other monogenic diseases characterized by premature termination codons.

Altered Respiratory Microbiomes, Plasma Metabolites, and Immune Responses in Influenza A Virus and Methicillin-Resistant Staphylococcus aureus Coinfection.

Influenza A virus (IAV)-methicillin-resistant Staphylococcus aureus (MRSA) coinfection causes severe respiratory infections. The host microbiome plays an important role in respiratory tract infections. However, the relationships among the immune responses, metabolic characteristics, and respiratory microbial characteristics of IAV-MRSA coinfection have not been fully studied. We used specific-pathogen-free (SPF) C57BL/6N mice infected with IAV and MRSA to build a nonlethal model of IAV-MRSA coinfection and characterized the upper respiratory tract (URT) and lower respiratory tract (LRT) microbiomes at 4 and 13 days postinfection by full-length 16S rRNA gene sequencing. Immune response and plasma metabolism profile analyses were performed at 4 days postinfection by flow cytometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relationships among the LRT microbiota, the immune response, and the plasma metabolism profile were analyzed by Spearman's correlation analysis. IAV-MRSA coinfection showed significant weight loss and lung injury and significantly increased loads of IAV and MRSA in bronchoalveolar lavage fluid (BALF). Microbiome data showed that coinfection significantly increased the relative abundances of Enterococcus faecalis, Enterobacter hormaechei, Citrobacter freundii, and Klebsiella pneumoniae and decreased the relative abundances of Lactobacillus reuteri and Lactobacillus murinus. The percentages of CD4+/CD8+ T cells and B cells in the spleen; the levels of interleukin-9 (IL-9), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8 in the lung; and the level of mevalonolactone in plasma were increased in IAV-MRSA-coinfected mice. L. murinus was positively correlated with lung macrophages and natural killer (NK) cells, negatively correlated with spleen B cells and CD4+/CD8+ T cells, and correlated with multiple plasma metabolites. Future research is needed to clarify whether L. murinus mediates or alters the severity of IAV-MRSA coinfection. IMPORTANCE The respiratory microbiome plays an important role in respiratory tract infections. In this study, we characterized the URT and LRT microbiota, the host immune response, and plasma metabolic profiles during IAV-MRSA coinfection and evaluated their correlations. We observed that IAV-MRSA coinfection induced severe lung injury and dysregulated host immunity and plasma metabolic profiles, as evidenced by the aggravation of lung pathological damage, the reduction of innate immune cells, the strong adaptation of the immune response, and the upregulation of mevalonolactone in plasma. L. murinus was strongly correlated with immune cells and plasma metabolites. Our findings contribute to a better understanding of the role of the host microbiome in respiratory tract infections and identified a key bacterial species, L. murinus, that may provide important references for the development of probiotic therapies.

Groundwater constituents and the incidence of kidney cancer.

BACKGROUND: Kidney cancer incidence demonstrates significant geographic variation suggesting a role for environmental risk factors. This study sought to evaluate associations between groundwater exposures and kidney cancer incidence. METHODS: The authors identified constituents from 18,506 public groundwater wells in all 58 California counties measured in 1996-2010, and obtained county-level kidney cancer incidence data from the California Cancer Registry for 2003-2017. The authors developed a water-wide association study (WWAS) platform using XWAS methodology. Three cohorts were created with 5 years of groundwater measurements and 5-year kidney cancer incidence data. The authors fit Poisson regression models in each cohort to estimate the association between county-level average constituent concentrations and kidney cancer, adjusting for known risk factors: sex, obesity, smoking prevalence, and socioeconomic status at the county level. RESULTS: Thirteen groundwater constituents met stringent WWAS criteria (a false discovery rate <0.10 in the first cohort, followed by p values <.05 in subsequent cohorts) and were associated with kidney cancer incidence. The seven constituents directly related to kidney cancer incidence (and corresponding standardized incidence ratios) were chlordane (1.06; 95% confidence interval [CI], 1.02-1.10), dieldrin (1.04; 95% CI, 1.01-1.07), 1,2-dichloropropane (1.04; 95% CI, 1.02-1.05), 2,4,5-TP (1.03; 95% CI, 1.01-1.05), glyphosate (1.02; 95% CI, 1.01-1.04), endothall (1.02; 95% CI, 1.01-1.03), and carbaryl (1.02; 95% CI, 1.01-1.03). Among the six constituents inversely related to kidney cancer incidence, the standardized incidence ratio furthest from the null was for bromide (0.97; 95% CI, 0.94-0.99). CONCLUSIONS: This study identified several groundwater constituents associated with kidney cancer. Public health efforts to reduce the burden of kidney cancer should consider groundwater constituents as environmental exposures that may be associated with the incidence of kidney cancer.

Analysis of metal(loid) pollution and possibilities of electrokinetic phytoremediation of abandoned coking plant soil.

In this study, the spatial distribution of eight metal(loid)s in the soil of an abandoned coking plant in Shanxi, China, was mapped, and the ecological and health risks of the coking plant were assessed. The results showed that the soil Pb content of the coking plant greatly exceeded the background value, and Hg, Cd and Pb were the most polluting factors contributing to the considerable ecological risk level. There was also a non-carcinogenic risk in the coking plant, in which oral intake was the main pathway, and As, Pb and Cr were the main contributors. As the main contributor to ecological risk and non-carcinogenic risks and the most polluting metal, Pb was selected as a priority pollutant in the coking plant. Based on the detected concentration of Pb in the coking plant soil and in consideration of phytostabilization, ryegrass, alfalfa and castor were employed to study the phytoremediation and electrokinetic-enhanced phytoremediation effect in a series of Pb-contaminated soils (0, 100, 200, 300 and 400 mg/kg). It was found that the underground parts of alfalfa and castor had stronger Pb enrichment ability, and their biomass and Pb absorption capacity were improved in electrokinetic remediation methods. The Pb absorption capacities of the tested plants and the promotion efficiencies of electrokinetic-enhanced phytoremediation followed the order castor > ryegrass > alfalfa. Under the optimal electrical conditions, the remediation efficiency of castor was increased by 106 %, 83 %, 51 % and 48 % in 100, 200, 300, and 400 mg/kg Pb-contaminated soils, respectively.

A high-fidelity RNA-targeting Cas13 restores paternal Ube3a expression and improves motor functions in Angelman syndrome mice.

Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. No gene-specific treatment is available for patients so far. Although intact and transcriptionally active, paternally inherited UBE3A is silenced by elongation of antisense long noncoding RNA UBE3A-ATS in neurons. Here, we demonstrated that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPR-Cas13 (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in the cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter-driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to 4 months after treatment. Behavioral tests showed that expression of paternal Ube3a significantly alleviated AS-related symptoms, including obesity and motor function. Our results suggested that hfCas13x.1-mediated suppression of the Ube3a-ATS lncRNA potentially serves as a promising targeted intervention for AS.

Expressional and prognostic value of HPCAL1 in cholangiocarcinoma via integrated bioinformatics analyses and experiments.

BACKGROUND: Hippocalcin-like 1 (HPCAL1) is involved in the development of several cancer types. However, our understanding of the HPCAL1 activity in cholangiocarcinoma (CCA) remains limited. METHODS: Two microarray datasets were used to screen for differentially expressed genes (DEGs) involved in the development of CCA. The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) database was integrated to determine the prognostic significance of DEGs in CCA. The association between clinical characteristics and HPCAL1 expression levels was initially explored to assess the clinical profile of CCA. The prognostic value of HPCAL1 overexpression in the validation cohort was analyzed, followed by Gene Ontology (GO) term analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of HPCAL1. RESULTS: Three upregulated genes and 10 downregulated genes were detected from two microarray-based screenings. High expression of HPCAL1 as a poor prognostic factor of CCA was validated using TCGA/GEO integrated database and our database. Univariate and multivariate analyses along with Kaplan-Meier survival analysis showed that high HPCAL1 expression was an independent factor affecting the overall survival and relapse-free survival in patients with CCA. The high expression of HPCAL1 was significantly associated with cancer antigen 125 (CA-125) levels, number of tumors, lymph node invasion, and TNM stage. Analysis of the enriched GO terms and KEGG pathways revealed that the high expression of HPCAL1 was involved in the critical biological processes and molecular pathways, including modulation by a host of symbiont processes, the clathrin coat, actinin binding, and Rap1 signaling pathways. CONCLUSION: HPCAL1 was enriched in CCA in our study and has the potential to be applied in the identification of patients with CCA with an unfavorable prognosis.