Contrast-enhanced ultrasound with microbubbles containing sulfur hexafluoride and perfluorobutane with Kupffer phase for the detection of colorectal liver metastases.

OBJECTIVE: To compare contrast-enhanced ultrasound (CEUS) with microbubbles containing sulfur hexafluoride (SHF) and perfluorobutane (PFB) for the detection of colorectal liver metastasis (CRLM). METHODS: In this prospective study, conducted from September to November 2021, patients with colorectal cancer were consecutively recruited and underwent same-day ultrasound, SHF-CEUS, and PFB-CEUS. The reference standard was contrast-enhanced MRI and follow-up imaging. The size, depth, echogenicity, and calcification of each focal liver lesion were recorded. The number and conspicuity of CRLMs, based on washout appearance during the late phase (LP) (> 120 s)/Kupffer phase (KP), were evaluated offsite by two blinded readers. RESULTS: Overall, 230 lesions (CRLMs, n = 219; benign lesions, n = 11) in 78 patients were evaluated. Lesion conspicuity (p = 0.344) and accuracy in the detection of CRLM were comparable for SHF- and PFB-CEUS (0.877 for SHF vs. 0.770 for PFB, p = 0.087). More CRLMs ≥ 10 mm were identified by LP contrast washout in SHF-CEUS than in KP PFB-CEUS (p < 0.001). More CRLMs < 10 mm were identified by KP washout in PFB-CEUS than in LP SHF-CEUS (p < 0.001). Conspicuity was better on PFB-CEUS than on SHF-CEUS (p = 0.027). In hyperechoic lesions, lesions located deeper than 80 mm, and calcified lesions, CRLM conspicuity on PFB-CEUS was inferior to that on SHF-CEUS (p < 0.05). CONCLUSIONS: The overall accuracy of detection and conspicuity of washout in CRLMs were comparable between SHF and PFB-CEUS. PFB-CEUS has the advantage of identifying washout in small CRLMs. However, larger, hyperechogenic, deep-seated, or calcified lesions were better identified using SHF-CEUS. CLINICAL RELEVANCE STATEMENT: Accuracy of detection and conspicuity of washout in CRLMs were comparable between SHF- and PFB-CEUS. PFB-CEUS has the advantage in detecting small CRLMs, whereas SHF-CEUS is better for detecting larger, hyperechogenic, deep-seated, or calcified lesions. KEY POINTS: Contrast-enhanced ultrasound with sulfur hexafluoride in the late phase and perfluorobutane microbubbles in the Kupffer phase were comparable in terms of accuracy in the detection and conspicuity of colorectal liver metastases. Small colorectal liver metastases (< 10 mm) were more often identified in the Kupffer phase contrast-enhanced ultrasound imaging when using perfluorobutane microbubbles. Larger, hyperechogenic, deep-seated, or calcified lesions were better identified in the late phase contrast-enhanced ultrasound imaging (> 120 s) when using sulfur hexafluoride microbubbles.

Gamma-glutamyl transferase to aspartate aminotransferase ratio (GSR) predicts prognoses in patients with colorectal cancer with liver metastasis after microwave ablation.

BACKGROUND: Microwave ablation (MWA) is widely used to eliminate colorectal liver metastases (CRLM). However, the risk of tumor recurrence is difficult to predict due to lack of reliable clinical and biological markers. Elevation of gamma-glutamyl transferase (GGT) and aspartate transaminase (AST) provides signals for liver inflammation and cancer progression. The present study evaluated the association between pre-ablation GGT to AST ratio index (GSR) and hepatic recurrence in patients with CRLM after MWA. METHODS: A retrospectively analyzed 192 CRLM patients who underwent MWA from January 2013 to December 2017. Pre-ablation GSR was classified into high (≤ 2.34) or low (> 2.34) using the upper quartile value. The prognostic value of GSR and other risk factors for liver progression-free survival (LPFS) and cancer-specific survival (CSS) were evaluated by univariate and multivariate analyses. RESULTS: High GSR was significantly associated with males (P = 0.041), the presence of cholelithiasis (P = 0.012), but not pre-ablation chemotherapy (P = 0.355), which caused significantly increased levels of GGT (P = 0.015) and AST (P = 0.008). GSR showed a significant association with LPFS and CSS through univariate analysis (P = 0.002 and 0.006) and multivariate analysis (P = 0.043 and 0.037). The subgroup analysis demonstrated no interaction between GSR and all variables except for distribution in the sub-analysis of LPFS. CONCLUSIONS: Our findings suggest that the pre-ablation GSR can be considered as a promising prognostic indicator for poor prognosis of patients with CRLM underwent MWA. TRIAL REGISTRATION: Not applicable.

Prediction model for lateral lymph node metastasis of papillary thyroid carcinoma in children and adolescents based on ultrasound imaging and clinical features: a retrospective study.

BACKGROUND: The presence of lateral lymph node metastases (LNM) in paediatric patients with papillary thyroid cancer (PTC) is an independent risk factor for recurrence. We aimed to identify risk factors and establish a prediction model for lateral LNM before surgery in children and adolescents with PTC. METHODS: We developed a prediction model based on data obtained from 63 minors with PTC between January 2014 and June 2023. We collected and analysed clinical factors, ultrasound (US) features of the primary tumour, and pathology records of the patients. Multivariate logistic regression analysis was used to determine independent predictors and build a prediction model. We evaluated the predictive performance of risk factors and the prediction model using the area under the receiver operating characteristic (ROC) curve. We assessed the clinical usefulness of the predicting model using decision curve analysis. RESULTS: Among the minors with PTC, 21 had lateral LNM (33.3%). Logistic regression revealed that independent risk factors for lateral LNM were multifocality, tumour size, sex, and age. The area under the ROC curve for multifocality, tumour size, sex, and age was 0.62 (p = 0.049), 0.61 (p = 0.023), 0.66 (p = 0.003), and 0.58 (p = 0.013), respectively. Compared to a single risk factor, the combined predictors had a significantly higher area under the ROC curve (0.842), with a sensitivity and specificity of 71.4% and 81.0%, respectively (cutoff value = 0.524). Decision curve analysis showed that the prediction model was clinically useful, with threshold probabilities between 2% and 99%. CONCLUSIONS: The independent risk factors for lateral LNM in paediatric PTC patients were multifocality and tumour size on US imaging, as well as sex and age. Our model outperformed US imaging and clinical features alone in predicting the status of lateral LNM.

Acute kidney injury comorbidity analysis based on international classification of diseases-10 codes.

OBJECTIVE: Acute kidney injury (AKI) is a clinical syndrome that occurs as a result of a dramatic decline in kidney function caused by a variety of etiological factors. Its main biomarkers, serum creatinine and urine output, are not effective in diagnosing early AKI. For this reason, this study provides insight into this syndrome by exploring the comorbidities of AKI, which may facilitate the early diagnosis of AKI. In addition, organ crosstalk in AKI was systematically explored based on comorbidities to obtain clinically reliable results. METHODS: We collected data from the Medical Information Mart for Intensive Care-IV database on patients aged [Formula: see text] 18 years in intensive care units (ICU) who were diagnosed with AKI using the criteria proposed by Kidney Disease: Improving Global Outcomes. The Apriori algorithm was used to mine association rules on the diagnoses of 55,486 AKI and non-AKI patients in the ICU. The comorbidities of AKI mined were validated through the Electronic Intensive Care Unit database, the Colombian Open Health Database, and medical literature, after which comorbidity results were visualized using a disease network. Finally, organ diseases were identified and classified from comorbidities to investigate renal crosstalk with other distant organs in AKI. RESULTS: We found 579 AKI comorbidities, and the main ones were disorders of lipoprotein metabolism, essential hypertension, and disorders of fluid, electrolyte, and acid-base balance. Of the 579 comorbidities, 554 were verifiable and 25 were new and not previously reported. In addition, crosstalk between the kidneys and distant non-renal organs including the liver, heart, brain, lungs, and gut was observed in AKI with the strongest heart-kidney crosstalk, followed by lung-kidney crosstalk. CONCLUSION: The comorbidities mined in this study using association rules are scientific and may be used for the early diagnosis of AKI and the construction of AKI predictive models. Furthermore, the organ crosstalk results obtained through comorbidities may provide supporting information for the management of short- and long-term treatment practices for organ dysfunction.

Glycosylated AIE-active Red Light-triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy.

Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near-infrared light-triggered photolysis process of current photocage is largely singlet oxygen (1O2)-dependent and lack of compatibility with other reactive oxygen species (ROS)-activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT-LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY-TPE fluorophore via the superoxide anion radical (O2-•)-cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT-LRC could be self-assembled into aggregation-induced emission (AIE)-active nanoparticles (BT-LRCs) owing to the regulation of carbohydrate-carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT-LRCs could simultaneously generate abundant O2-• through the aggregation modulated by lactose interactions, and DNA-damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor-bearing mice. Furthermore, the inherent AIE property of BT-LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real-time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.

Whole-Genome Resequencing of Worldwide Wild and Domestic Sheep Elucidates Genetic Diversity, Introgression, and Agronomically Important Loci.

Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (∼16.10×) whole genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, ∼121.2 million single nucleotide polymorphisms, ∼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration, and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7,068,586C) in the 3'-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed prehistorical migrations from the Near Eastern domestication center to South-and-Southeast Asia and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation, and selection of sheep.

Outcomes Following Different Thermal Ablation Strategies in Patients with Unresectable Colorectal Liver Metastases.

Background For patients with unresectable colorectal liver metastases (CRLM), clinical guidelines recommend imaging-guided thermal ablation combined with systemic therapy. However, the optimal thermal ablation strategy remains unclear. Purpose To compare long-term outcomes between patients who underwent upfront ablation or delayed ablation for unresectable CRLM. Materials and Methods This retrospective study included patients with unresectable CRLM (three or fewer lesions; diameter, <3 cm) admitted to one of seven hospitals between October 2009 and December 2020. Upfront ablation was performed 2-4 weeks before the start of systemic therapy, and delayed ablation was performed 2-3 months after the start of systemic therapy. Propensity score matching was applied to adjust for differences in baseline variables between groups. Disease-free survival (DFS) was the primary outcome. Overall survival (OS), complications, and adverse events were secondary outcomes. Outcomes were compared between groups by using the log-rank test. Results In total, 255 patients who underwent delayed ablation (mean age, 57 years ± 11 [SD]; 184 men [72%]) and 103 patients who underwent upfront ablation (mean age, 56 years ± 12; 72 men [70%]) were included. After propensity score matching (n = 100 in both groups), the 5-year DFS for patients who underwent upfront ablation was better compared with patients who underwent delayed ablation (36% vs 21%; P = .02). For 5-year OS, no evidence of a difference was observed between ablation strategies (delayed ablation, 59% vs upfront ablation, 64%; P = .49). Additionally, no differences were observed between ablation strategies with respect to the rates of ablative complications (delayed ablation, 6% vs upfront ablation, 5%; P = .76) or drug-related adverse events (delayed and upfront ablation both 9%; P = .99). Conclusion In patients with relatively few (three or fewer) and small (<3 cm) unresectable CRLM, upfront thermal ablation combined with adjuvant systemic therapy led to better DFS compared with delayed ablation. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Prevalent Pseudoprogression and Pseudoresidue in Patients With Rectal Cancer Treated With Neoadjuvant Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitor (ICI) treatment in patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) tumors holds promise in reshaping organ preservation in rectal cancer. However, the benefits are accompanied by distinctive patterns of response, introducing a dilemma in the response evaluation for clinical decision-making. PATIENTS AND METHODS: Patients with locally advanced rectal cancer with MSI-H/dMMR tumors receiving neoadjuvant ICI (nICI) treatment (n=13) and matched patients receiving neoadjuvant chemoradiotherapy (nCRT; n=13) were included to compare clinical response and histopathologic features. RESULTS: Among the 13 patients receiving nICI treatment, in the final radiologic evaluation prior to surgery (at a median of 103 days after initiation of therapy), progressive disease (n=3), stable disease (n=1), partial response (n=7), and complete response (n=2) were observed. However, these patients were later confirmed as having pathologic complete response, resulting in pseudoprogression and pseudoresidue with incidences of 23.1% (n=3) and 76.9% (n=10), respectively, whereas no pseudoprogression was found in the 13 patients receiving nCRT. We further revealed the histopathologic basis underlying the pseudoprogression and pseudoresidue by discovering the distinctive immune-related regression features after nICI treatment, including fibrogenesis, dense lymphocytes, and plasma cell infiltration. CONCLUSIONS: Pseudoprogression and pseudoresidue were unique and prevalent response patterns in MSI-H/dMMR rectal cancer after nICI treatment. Our findings highlight the importance of developing specific strategies for response evaluation in neoadjuvant immunotherapy to identify patients with a good response in whom sphincter/organ-preserving or watch-and-wait strategies may be considered.

Up-Front Versus Delayed Thermal Ablation for Colorectal Liver Oligometastases: A Multicenter Retrospective Study Using Propensity Score Matching.

BACKGROUND. Thermal ablation combined with systemic therapy is an accepted treatment of colorectal liver oligometastases (CLOM). Consensus is lacking regarding the optimal timing of thermal ablation relative to systemic therapy. OBJECTIVE. The purpose of our study was to compare delayed and up-front thermal ablation in terms of efficacy and safety in the treatment of patients with CLOM. METHODS. This retrospective multicenter study included 440 patients (316 men, 124 women; mean age, 57.1 ± 11.1 [SD] years) with CLOM from nine hospitals between October 2009 and December 2020. Patients underwent delayed (n = 322) or up-front (n = 118) thermal ablation in combination with systemic therapy. Analyses included all patients using crude data, all patients using inverse probability treatment weighting (IPTW), and a subset of patients using propensity score matching (PSM) at a 1:1 ratio to balance baseline variables (108 matched patients for each group [i.e., delayed ablation and up-front ablation]). Patients were classified as having a low or high tumor burden score (TBS) on the basis of the number and size of the liver metastases. The primary outcome was progression-free survival (PFS); secondary outcomes included overall survival (OS), complications from ablation, and adverse events (AEs) from systemic therapy. Survival analysis used the Kaplan-Meier method. RESULTS. The median follow-up was 2.9 years. The 5-year PFS was 17.1% for delayed ablation versus 33.6% for up-front ablation in all patients and 17.9% versus 34.7% after PSM. Delayed ablation was associated with worse PFS in the crude analysis (HR = 0.62), IPTW analysis (HR = 0.66), and PSM analysis (HR = 0.62) (all p < .05). No analysis showed a significant difference in OS between delayed and up-front ablation. Crude, IPTW, and PSM analyses showed better PFS for up-front compared with delayed ablation in patients with a low TBS (HR = 0.62-0.67; all p < .05); none of these analyses showed significant difference in PFS in patients with a high TBS. Delayed ablation and up-front ablation groups showed no difference in frequency of grade III or IV ablation complications (4.7% vs 6.8%, p = .38) or grade III or IV systemic therapy AEs (12.4% vs 10.2%, p = .53). CONCLUSION. In patients with CLOM, up-front ablation achieved better PFS compared with delayed ablation, although only among patients with a low TBS. CLINICAL IMPACT. These findings could help optimize clinical implementation of thermal ablation in patients who are not candidates for surgical resection.

Percutaneous ablation of colorectal liver metastases: a comparison between the outcomes of grayscale US guidance and Sonazoid CEUS Kupffer phase guidance using propensity score matching.

PURPOSE: To assess the utility of Sonazoid contrast-enhanced ultrasound (CEUS) for guiding percutaneous microwave ablation (MWA) for colorectal liver metastases (CRLMs). MATERIALS AND METHODS: The medical records of patients who had undergone ultrasound (US)-guided percutaneous MWA between July 2020 and June 2022, were reviewed. Propensity score matching (PSM) with a ratio of 1:1 was used to balance the potential bias between the grayscale US-guided and Sonazoid CEUS-guided groups. Local tumor progression (LTP), intrahepatic recurrence (IR), and complication rates were compared between the two groups. RESULTS: Of 252 patients enrolled, 247 achieved complete ablation, and the technical effectiveness was 98.0% (247/252). Of these 247 patients, 158 were in the grayscale US-guided group and 89 in the Sonazoid CEUS-guided group. The median follow-up period was 14.6 months. After PSM, there were no significant differences in LTP, IR, or complication rates between the two groups (p = 0.100, p = 0.511, p > 0.99, respectively). Multivariate analysis identified tumor size ≥ 3 cm (hazard ratio [HR], 7.945; 95% CI, 2.591-24.370; p < 0.001), perivascular (HR, 2.331; 95% CI, 1.068-5.087; p = 0.034), and tumor depth > 8 cm (HR, 3.194; 95% CI, 1.439-7.091; p = 0.004) as significant factors associated with LTP. For tumors with poor vision on grayscale US, Sonazoid CEUS-guided ablation achieved a better LTP rate than grayscale US-guided ablation (3.7% vs.14.8%, p = 0.032). CONCLUSION: For tumors with poor vision on grayscale US, Sonazoid CEUS guidance is recommended for better local tumor control.

Malignant transformation of rectal endometriosis: Preoperative diagnosis by endorectal ultrasound guided biopsy.

The prevalence of malignant transformation of endometriotic lesions is estimated between 0.3% and 1%. Malignant transformations of endometriosis occur in the colorectum is rarer, accounting for 0.25%. Because the malignant transformation of colorectal endometriosis rarely involves mucosa, it is difficult to obtain abnormal tissue by routine endoscopic biopsy. In this case, we evaluated a patient with a rectal mass by endorectal ultrasound (ERUS) and performed endorectal ultrasound-guided biopsy (EGB). Malignant transformations of endometriosis were confirmed by histological result. For patients with rectal tumors but with negative findings on colonoscopy and biopsy, ERUS and EGB contribute to preoperative diagnosis.

In Situ Self-Assembled J-Aggregate Nanofibers of Glycosylated Aza-BODIPY for Synergetic Cell Membrane Disruption and Type†I Photodynamic Therapy.

The in situ self-assembly of exogenous molecules is a powerful strategy for manipulating cellular behavior. However, the direct self-assembly of photochemically inert constituents into supramolecular nano-photosensitizers (PSs) within cancer cells for precise photodynamic therapy (PDT) remains a challenge. Herein, we developed a glycosylated Aza-BODIPY compound (LMBP) capable of self-assembling into J-aggregate nanofibers in situ for cell membrane destruction and type I PDT. LMBP selectively entered human hepatocellular carcinoma HepG2 cells and subsequently self-assembled into intracellular J-aggregate nanovesicles and nanofibers through supramolecular interactions. Detailed studies revealed that these J-aggregate nanostructures generated superoxide radicals (O2 - ⋅) exclusively through photoinduced electron transfer, thus enabling effective PDT. Furthermore, the intracellular nanofibers exhibited an aggregation-induced retention effect, which resulted in selective toxicity to HepG2 cells by disrupting their cellular membranes and synergizing with PDT for powerful tumor suppression efficacy in vivo.

A prognostic nomogram for intrahepatic progression-free survival in patients with colorectal liver metastases after ultrasound-guided percutaneous microwave ablation.

PURPOSE: The present study identified predictors of intrahepatic progression-free survival (ihPFS) after ultrasound (US)-guided percutaneous microwave ablation (MWA) for colorectal liver metastases (CRLMs) and developed a nomogram to predict ihPFS. METHODS: From January 2013 to December 2018, a total of 314 patients (224 men and 90 women; mean age, 57.1 ± 11.8 years; range, 23-86 years) with 645 CRLMs (mean diameter, 16.6 ± 6.5 mm; range, 6.0-45.0 mm) treated with US-guided percutaneous MWA were included and analyzed. The average number of CRLMs per patient treated was 2 (range, 1-8). A nomogram to predict ihPFS was developed based on a multivariable Cox model. Validation of the nomogram was performed using the concordance index (C-index), calibration curves, and decision curve analyses. RESULTS: The 1-, 2-, and 3-year cumulative ihPFS rates were 59.0%, 38.9%, and 30.8%, respectively. Maximal CRLM size, number of CRLMs, ablative margin, primary tumor lymph node status, and chemotherapy were five independent prognostic factors for ihPFS. The C-index of the nomogram was 0.702 (CI: 0.681-0.723). A risk classification system that perfectly classified the patients into three risk groups was constructed. The median ihPFS of patients in the low-, intermediate-, and high-risk groups was 36.3 months (95% CI: 21.4-51.1), 13.4 months (95% CI: 12.1-14.6), and 3.8 months (95% CI: 2.3-5.3), respectively. CONCLUSION: The nomogram and risk classification system will facilitate the personalized assessment of ihPFS for patients receiving US-guided percutaneous MWA for CRLMs.

Nephrotic syndrome of minimal change disease following exposure to mercury-containing skin lightening cream: A case report and literature review.

Long-term exposure to mercury-containing skin lightening cream can cause mercury-related nephropathy, among which, membranous nephropathy (MN) and minimal change disease (MCD) are the main pathological types. In contrast to these two conditions, MCD with IgA deposition is not a common disease. In the present study, we report a 65-year-old Asian woman who developed nephrotic syndrome following long-term use of mercury-containing skin lightening cream. The urine mercury level of the patient was significantly increased, and the results of the renal biopsy indicated diagnosis of MCD with IgA deposition. Following three courses of treatment with sodium dimercaptopropane sulfonate (DMPS) alone and discontinuation of the skin cream, the symptoms of the patient were relieved without use of glucocorticoids, with proteinuria turning negative and a significant reduction in urine mercury levels. During the 6-month follow-up period, routine urinalysis remained normal. By reviewing relevant published literature, we summarized the pathological characteristics, possible mechanism of action, and treatment strategies of mercury poisoning-related MCD. The possibility of mercury poisoning should be considered for patients with nephropathy and history of use of skin lightening cosmetics. In these patients, the urine mercury levels should be measured in time so that mercury removal therapy can be implemented early.

Genomic Mechanisms of Physiological and Morphological Adaptations of Limestone Langurs to Karst Habitats.

Knowledge of the physiological and morphological evolution and adaptation of nonhuman primates is critical to understand hominin origins, physiological ecology, morphological evolution, and applications in biomedicine. Particularly, limestone langurs represent a direct example of adaptations to the challenges of exploiting a high calcium and harsh environment. Here, we report a de novo genome assembly (Tfra_2.0) of a male François's langur (Trachypithecus francoisi) with contig N50 of 16.3 Mb and resequencing data of 23 individuals representing five limestone and four forest langur species. Comparative genomics reveals evidence for functional evolution in genes and gene families related to calcium signaling in the limestone langur genome, probably as an adaptation to naturally occurring high calcium levels present in water and plant resources in karst habitats. The genomic and functional analyses suggest that a single point mutation (Lys1905Arg) in the α1c subunit of the L-type voltage-gated calcium channel Cav1.2 (CACNA1C) attenuates the inward calcium current into the cells in vitro. Population genomic analyses and RNA-sequencing indicate that EDNRB is less expressed in white tail hair follicles of the white-headed langur (T. leucocephalus) compared with the black-colored François's langur and hence might be responsible for species-specific differences in body coloration. Our findings contribute to a new understanding of gene-environment interactions and physiomorphological adaptative mechanisms in ecologically specialized primate taxa.

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild-Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial.

PURPOSE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two-group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver-limited metastases (CLM) and BRAF/RAS wild-type. PATIENTS AND METHODS: Patients were enrolled to receive cetuximab (500 mg/m2 ) plus mFOLFOXIRI (oxaliplatin 85 mg/m2 , irinotecan 165 mg/m2 , folinic acid 400 mg/m2 , 5-fluorouracil 2,800 mg/m2 46-hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety. RESULTS: Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%-48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%-36.4%; p = .010) compared with those in control group. Progression-free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups. CONCLUSION: Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM. IMPLICATIONS FOR PRACTICE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver-limited metastases and BRAF/RAS wild-type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression-free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver-limited metastasis.

Residues R1075, D1090, R1095, and C1130 Are Critical in ADAMTS13 TSP8-Spacer Interaction Predicted by Molecular Dynamics Simulation.

ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats, member 13) cleaves von Willebrand Factor (VWF) multimers to limit the prothrombotic function of VWF. The deficiency of ADAMTS13 causes a lethal thrombotic microvascular disease, thrombotic thrombocytopenic purpura (TTP). ADAMTS13 circulates in a "closed" conformation with the distal domain associating the Spacer domain to avoid off-target proteolysis or recognition by auto-antibodies. However, the interactions of the distal TSP8 domain and the Spacer domain remain elusive. Here, we constructed the TSP8-Spacer complex by a combination of homology modelling and flexible docking. Molecular dynamics simulation was applied to map the binding sites on the TSP8 or Spacer domain. The results predicted that R1075, D1090, R1095, and C1130 on the TSP8 domain were key residues that interacted with the Spacer domain. R1075 and R1095 bound exosite-4 tightly, D1090 formed multiple hydrogen bonds and salt bridges with exosite-3, and C1130 interacted with both exosite-3 and exosite-4. Specific mutations of exosite-3 (R568K/F592Y/R660K/Y661F/Y665F) or the four key residues (R1075A/D1090A/R1095A/C1130A) impaired the binding of the TSP8 domain to the Spacer domain. These results shed new light on the understanding of the auto-inhibition of ADAMTS13.

Genome resequencing reveals demographic history and genetic architecture of seed salinity tolerance in Populus euphratica.

Populus euphratica is a dominant tree species in desert riparian forests and possesses extraordinary adaptation to salinity stress. Exploration of its genomic variation and molecular underpinning of salinity tolerance is important for elucidating population evolution and identifying stress-related genes. Here, we identify approximately 3.15 million single nucleotide polymorphisms using whole-genome resequencing. The natural populations of P. euphratica in northwest China are divided into four distinct clades that exhibit strong geographical distribution patterns. Pleistocene climatic fluctuations and tectonic deformation jointly shaped the extant genetic patterns. A seed germination rate-based salinity tolerance index was used to evaluate seed salinity tolerance of P. euphratica and a genome-wide association study was implemented. A total of 38 single nucleotide polymorphisms were associated with seed salinity tolerance and were located within or near 82 genes. Expression profiles showed that most of these genes were regulated under salt stress, revealing the genetic complexity of seed salinity tolerance. Furthermore, DEAD-box ATP-dependent RNA helicase 57 and one undescribed gene (CCG029559) were demonstrated to improve the seed salinity tolerance in transgenic Arabidopsis. These results provide new insights into the demographic history and genetic architecture of seed salinity tolerance in desert poplar.

Network analysis of autistic disease comorbidities in Chinese children based on ICD-10 codes.

BACKGROUND: Autism is a lifelong disability associated with several comorbidities that confound diagnosis and treatment. A better understanding of these comorbidities would facilitate diagnosis and improve treatments. Our aim was to improve the detection of comorbid diseases associated with autism. METHODS: We used an FP-growth algorithm to retrospectively infer disease associations using 1488 patients with autism treated at the Guangzhou Women and Children's Medical Center. The disease network was established using Cytoscape 3.7. The rules were internally validated by 10-fold cross-validation. All rules were further verified using the Columbia Open Health Data (COHD) and by literature search. RESULTS: We found 148 comorbid diseases including intellectual disability, developmental speech disorder, and epilepsy. The network comprised of 76 nodes and 178 directed links. 158 links were confirmed by literature search and 105 links were validated by COHD. Furthermore, we identified 14 links not previously reported. CONCLUSION: We demonstrate that the FP-growth algorithm can detect comorbid disease patterns, including novel ones, in patients with autism.

Vision treatment strategy for acute blindness in adolescent female with diffuse leptomeningeal glioneuronal tumor.

Diffuse leptomeningeal glioneuronal tumor with the first symptom of acute rapid blindness in both eyes are rare in adolescents. We present a case of an adolescent female without a history of cancer who developed a dramatic loss of vision and eventually blindness, and was diagnosed as diffuse leptomeningeal glioneuronal tumor by cerebrospinal fluid cytology and enhanced MRI. In order to save vision, under the condition of ineffective dehydration treatment, timely emergency surgery to implant Ommaya sac drainage cerebrospinal fluid. According to the pathophysiological mechanism of cerebral edema, we added Edaravone to scavenge oxygen free radicals, Alprostadil to improve microcirculation, Monosialotetrahexosylganglioside nutrient nerve, Butylphthalide to promote collateral circulation, combined with hyperbaric oxygen and acupoint injection of Anisodine. Finally, the patient's vision returned to normal. Conclusion: when dehydration treatment is ineffective, timely surgery to reduce intracranial pressure, combined with comprehensive treatment, can effectively save vision.