Targeting DNA Damage and Repair Machinery via Delivering WEE1 Inhibitor and Platinum (IV) Prodrugs to Stimulate STING Pathway for Maximizing Chemo-Immunotherapy in Bladder Cancer.

Both cisplatin-based chemotherapy and immune checkpoint blockers (ICBs)-based immunotherapy are the first-line treatments for patients with advanced bladder cancer. Cancer cells can develop resistance to cisplatin through extensive DNA repair, while a low response rate to ICBs is mostly due to the presence of an immunosuppressive microenvironment and low PD-L1 expression. Herein, a glutathione (GSH)-responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) is designed. NP2 can be triggered by GSH in cancer cells, and the released MK1775 can inhibit the activity of WEE1 protein, which ultimately increases DNA damage by cisplatin. Genome-wide RNA sequencing first reveals that NP2 can inhibit DNA repair machinery by interfering with the cell cycle and significantly activate the stimulator of interferon genes pathway. Tumor growth is significantly inhibited by NP2 in vivo. As innate and adaptive immune responses are stimulated, the immunosuppressive microenvironment is modified, and the "immune cold tumor" is transformed into an "immune hot tumor". In addition, NP2 can upregulate PD-L1 expression in tumor cells, thereby increasing the response rate of PD-L1 monoclonal antibody (αPD-L1) and eliciting long-term immune responses in both primary and metastatic tumors.

Climate and industrial pollution determine the seasonal and spatial mercury variations in the China's Weihe River.

Natural processes and human activities impact mercury (Hg) pollution in rivers. Investigating the individual contributions and interactions of factors affecting variations in Hg concentrations, particularly under climate change, is crucial for safeguarding watershed ecosystems and human health. We collected 381 water samples from China's Weihe River Basin (WRB) during dry and wet seasons to assess the total Hg (THg) concentration. Results revealed high Hg concentrations in the WRB (0.1-2200.9 ng/L, mean 126.2 ± 335.5 ng/L), with higher levels during the wet season (wet season: 249.1 ± 453.5 ng/L, dry season: 12.7 ± 14.0 ng/L), particularly in the mainstream and southern tributaries of the Weihe River. Industrial pollution (contributing 26.2 %) and precipitation (contributing 33.5 %) drove spatial heterogeneity in THg concentrations during the dry and wet seasons, respectively. Notably, combined explanatory power increased to 47.9 % when interaction was considered, highlighting the amplifying effect of climate change, particularly precipitation, on the impact of industrial pollution. The middle and downstream of the Weihe River, especially the Guanzhong urban agglomeration, were identified as high-risk regions for Hg pollution. With ongoing climate change the risk of Hg exposure in the WRB is expected to escalate. This study lays a robust scientific foundation for the effective management of Hg pollution in analogous river systems worldwide.

Artificial intelligence in skeletal metastasis imaging.

In the field of metastatic skeletal oncology imaging, the role of artificial intelligence (AI) is becoming more prominent. Bone metastasis typically indicates the terminal stage of various malignant neoplasms. Once identified, it necessitates a comprehensive revision of the initial treatment regime, and palliative care is often the only resort. Given the gravity of the condition, the diagnosis of bone metastasis should be approached with utmost caution. AI techniques are being evaluated for their efficacy in a range of tasks within medical imaging, including object detection, disease classification, region segmentation, and prognosis prediction in medical imaging. These methods offer a standardized solution to the frequently subjective challenge of image interpretation.This subjectivity is most desirable in bone metastasis imaging. This review describes the basic imaging modalities of bone metastasis imaging, along with the recent developments and current applications of AI in the respective imaging studies. These concrete examples emphasize the importance of using computer-aided systems in the clinical setting. The review culminates with an examination of the current limitations and prospects of AI in the realm of bone metastasis imaging. To establish the credibility of AI in this domain, further research efforts are required to enhance the reproducibility and attain robust level of empirical support.

Extreme precipitation stable isotopic compositions reveal unexpected summer monsoon incursions in the Qilian Mountains.

Isotope composition and moisture sources of precipitation are important for understanding water cycles and reconstructing paleoclimate. Based on 15-years' precipitation stable Isotope composition (δ18O and δ2H) from four stations of the Qilian Mountains, we found unique δ18O and δ2H features associated with the incursion of the summer monsoon over the Qilian Mountains, northwestern China. In 12 of the 15 years, similar seasonal variations of δ18O and δ2H confirmed a dominant source of moisture from Westerly circulation, and higher intercepts of the local meteoric water line (LMWL) indicated strong recycling of continental moisture. However, in August 2016 and 2018, extremely low slopes and intercepts of the LMWL, and more negative δ18O and δ2H revealed substantial contributions of the Asian summer monsoon to precipitation of the Qilian Mountains, with extremely heavy precipitation in August 2016. The column moisture flux, land-sea thermal contrast, correlations of precipitation δ18O with East Asian Summer Monsoon Index and Westerlies Index, HYSPLIT modeling results and precipitation δ18O along backward trajectories confirmed incursions of the summer monsoon in August 2016 and 2018. Our redefining of the boundary of the summer monsoon region confirmed the summer monsoon incursion zone can extend to the west of longitude 96°E and north of latitude 40°N in strong monsoon years, corresponding to boundaries of monsoon incursions in the mid-Holocene. Temperature correlated with precipitation δ18O at monthly and shorter time scales, but not for whole seasons or at yearly scale, revealing that summer monsoon incursions are therefore more likely than changing temperature to explain the multi-year cycles in the Qilian Mountains ice archives. Continent-scale shifts in atmospheric circulation strongly influence water resources in the Qilian mountains, and may change in frequency as climate warms. This study therefore has important implications for understanding water resources in the Qilian mountains in the past and into the future.

Surgical treatment of a distal radius and ipsilateral metacarpal hemophilic pseudotumor without recurrence or functional deficit: a case report.

Background: Distal hemophilic pseudotumor (HP) occurring distal to the wrist appear to be secondary to intraosseous hemorrhage, which develops rapidly and should be treated primarily with long-term replacement therapy and cast immobilization. Surgical removal or even amputation is indicated when conservative management fails to prevent progression. Here, a practical strategy was described for those patients who cannot afford the cost of routine coagulation factor replacement therapy, namely immediate surgical curettage and bone grafting as well as continuous follow-up. Case description: A 7-year-old boy with a history of mild hemophilia A was admitted to our medical center because of a 2-year history of progressive swelling and pain around right forearm and hand. Coagulation factor VIII level was 11.1% of normal with no inhibitor. Radiographs revealed expansile swelling, bone destruction, and deformity of the distal right radius and the second metacarpal bone. He was diagnosed with distal HP. Surgical procedure of curettage and bone grafting was performed. The function and appearance of the right wrist were almost normal without discomfort at the 101-month follow-up. Significantly, the same patient was hospitalized again because of a year-long progressive swelling and pain around the left hand when he was 14 years old. X-ray showed multiple bone destruction of the left proximal phalanges of left thumb, middle finger and little finger with local pathological fractures. Surgical procedure of HPs including curettage and bone grafting was performed. Postoperative recovery was good, and the last clinical follow-up at 18 months after the operation displayed a satisfactory shape and functional outcomes. Conclusions: Curettage and bone grafting prove to be safe and feasible for patients with distal HP and continuous follow-up of patients with distal HP is very vital for timely finding and then treating successive HP in developing countries.

Long-term clinical outcomes following total knee arthroplasty in patients with hemophilic arthropathy: a single-surgeon cohort after a 10- to 17-year follow-up.

BACKGROUND: Total knee arthroplasty (TKA) can reduce severe joint pain and improve functional disability in hemophilia. However, the long-term outcomes have rarely been reported in China. Therefore, this study aimed to evaluate the long-term outcomes and complications of TKA in Chinese patients with hemophilic arthropathy. METHODS: We retrospectively reviewed patients with hemophilia who underwent TKA between 2003 and 2020, with at least 10 years of follow-up. The clinical results, patellar scores, patients' overall satisfaction ratings, and radiological findings were evaluated. Revision surgery for implants during the follow-up period was recorded. RESULTS: Twenty-six patients with 36 TKAs were successfully followed up for an average of 12.4 years. Their Hospital for Special Surgery Knee Score improved from an average of 45.8 to 85.9. The average flexion contracture statistically significantly decreased from 18.1° to 4.2°. The range of motion (ROM) improved from 60.6° to 84.8°. All the patients accepted patelloplasty, and the patients' patellar score improved from 7.8 preoperatively to 24.9 at the last follow-up. There was no statistically significant difference in clinical outcomes between the unilateral and bilateral procedures, except for a better ROM at follow-up in the unilateral group. Mild and enduring anterior knee pain was reported in seven knees (19%). The annual bleeding event was 2.7 times/year at the last follow-up. A total of 25 patients with 35 TKAs were satisfied with the procedure (97%). Revision surgery was performed in seven knees, with 10- and 15-year prosthesis survival rates of 85.8% and 75.7%, respectively. CONCLUSIONS: TKA is an effective procedure for patients with end-stage hemophilic arthropathy, which relieves pain, improves knee functions, decreases flexion contracture, and provides a high rate of satisfaction after more than ten years of follow-up.

The PUMCH Evaluation System of Idiopathic Normal Pressure Hydrocephalus and Clinical Practice.

OBJECTIVE: Differentiating idiopathic normal pressure hydrocephalus (iNPH) from other neurodegenerative diseases is challenging. Only a portion of the patients clinically suspected of iNPH would respond to surgical intervention. A cerebrospinal fluid (CSF) tap test is usually used to predict surgery outcomes and hence aid clinical decision-making, but the workup varies. We introduce the CSF tap test conducted at our center and examine its power by analyzing data from a series of iNPH cases that underwent shunt placement. We analyze common features in the past medical history of our patients and investigate whether they are related to the etiology of iNPH. METHODS: Data from 20 patients who were positive in the tap tests preoperatively and received ventriculoperitoneal shunting (VPS) were retrospectively analyzed. Preoperative and postoperative performance data were analyzed. History of any underlying medical conditions was taken into consideration. Patients with negative tap test results of the same period were also followed up. RESULTS: We performed VPS placement in 20 NPH patients from October 2019 to February 2022. Of these, 90% exhibited improvement in at least 1 of the clinical triad, proving the predictive power of the Peking Union Medical College Hospital test workflow. The underlying conditions like hypertension, diabetes and insufficiency in cerebral blood supply were also found to be associated with the onset of NPH. CONCLUSION: Our evaluation system is a valid tool for NPH assessment and can guide clinical decision-making. Comorbidities should be taken into consideration as they contribute to the pathogenesis and progression of NPH. Better identification of potential iNPH patients will lower the burden exerted on the family and the aging society.

Short-term and long-term outcomes in patients with cryptococcal meningitis after ventriculoperitoneal shunt placement.

Objective: The purpose of this study was to assess the short-term and long-term outcomes of ventriculoperitoneal shunt (VPS) placement in patients with cryptococcal meningitis (CM). Methods: We performed a retrospective analysis of all patients with CM admitted to the Peking Union Medical College Hospital from September 1990 to January 2021. We collected related clinical features to analyze the short- and long-term outcomes of VPS at 1 month and 1 year at least the following therapy, respectively. Overall survival (OS) was compared with all patients and a subgroup of critically ill cases by the Kaplan-Meier method with the log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazard model to identify statistically significant prognostic factors. Results: We enrolled 98 patients, fifteen of whom underwent VPS. Those who received VPS had a lower cerebrospinal fluid (CSF) Cryptococcus burden (1:1 vs. 1:16; p = 0.046), lower opening pressures (173.3 mmH2 O vs. 224 mmH2O; p = 0.009) at lumbar punctures, and a lower incidence of critical cases (6.7 vs. 31.3%; p = 0.049). According to our long-term follow-up, no significant difference was shown in the Barthel Index (BI) between the two groups. Two patients in the VPS group suffered postoperative complications and had to go through another revision surgery. According to survival analysis, overall survival (OS) between the VPS and non-VPS groups was not significantly different. However, the Kaplan-Meier plots showed that critical patients with VPS had better survival in OS (p < 0.009). Multivariable analyses for critical patients showed VPS was an independent prognostic factor. Conclusion: A VPS could reduce the intracranial pressure (ICP), decrease the counts of Cryptococcus neoformans by a faster rate and reduce the number of critical cases. The VPS used in critical patients with CM has a significant impact on survival, but it showed no improvement in the long-term Barthel Index (BI) vs. the conservative treatment and could lead to postoperative complications.

Case report: Drug rash with eosinophilia and systemic symptoms syndrome in a patient with anti-interferon-γ autoantibody-associated immunodeficiency.

A 56-year-old Chinese woman with previous disseminated mycobacterium avium complex infection and recurrent cervical abscesses from Burkholderia cepacia complex visited our hospital. She was diagnosed with adult-onset immunodeficiency (AOID) and tested positive for interferon-γ-neutralizing autoantibody. Ceftazidime was administered as the initial antimicrobial treatment, which was later combined with sulfamethoxazole-trimethoprim (SMZ-TMP). She developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome after SMZ-TMP administration and improved after withdrawal of the culprit antibiotic and systemic glucocorticoids treatment. Her cervical infection was eventually cured after combined therapy of long-term antibiotics and anti-IFN-γ autoantibodies (AIGA) titer-lowering treatments including glucocorticoids, rituximab, and plasmapheresis. This is the first case of DRESS syndrome in the setting of AIGA-induced AOID and is worthy of notice.

Self-Sacrificially Degradable Pseudo-Semiconducting Polymer Nanoparticles that Integrate NIR-II Fluorescence Bioimaging, Photodynamic Immunotherapy, and Photo-Activated Chemotherapy.

Semiconducting polymers (SP) hold great promise for cancer phototherapy due to their excellent optical properties; however, their clinical application is still hampered by their poor biodegradability. Herein, a self-sacrificially biodegradable pseudo-semiconducting polymer (PSP) for NIR-II fluorescence bioimaging, photodynamic immunotherapy, and photoactivated chemotherapy (PACT) is reported. The PSP can further co-assemble with an amphiphilic polyester with pendant doxorubicin (DOX) in its side chains via reactive oxygen species (ROS)-responsive thioketal linkages (PEDOX ), which are denoted as NP@PEDOX /PSP. The NP@PEDOX /PSP can accumulate at tumor sites and generate ROS for photodynamic immunotherapy as well as near-infrared-II fluorescence (NIR-II) for bioimaging upon irradition at 808 nm. The ROS could break up thioketal linkages in PEDOX , resulting in rapid doxorubicin (DOX) release for PACT. Finally, both PEDOX and PSP are degraded sacrificially by intracellular glutathione (GSH), resulting in the dissociation of NP@PEDOX /PSP. This work highlights the application of self-sacrificially degradable PSP for NIR-II fluorescence bioimaging, photodynamic immunotherapy, and PACT in cancer therapy.

The establishment of polypeptide PSMA-targeted chimeric antigen receptor-engineered natural killer cells for castration-resistant prostate cancer and the induction of ferroptosis-related cell death.

BACKGROUND: The mortality of castration-resistant prostate cancer (CRPC) is high due to lack of an effective treatment. Chimeric antigen receptor (CAR)-based therapy is a promising immunotherapeutic strategy. Here, we aimed to design a novel CAR-natural killer (NK) cells with a clinically significant tumoricidal effect on CRPC. METHODS: We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector. Different intracellular segments (CD244, NKG2D, or CD3ζ) were screened to identify the best candidate according to cell lysis assay and CD107a expression levels. To enhance the affinity of the CAR to the tumor antigen, we compared an antibody specific for prostate-specific membrane antigen (anti-PSMA) with PSMA-targeted polypeptide (p-PSMA), which was screened by phage display combinatorial library. Then, CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated. In addition, we verified their tumor-killing effect in vitro and in vivo. The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay. Moreover, ferroptosis-related cell death was explored as a possible underlying mechanism. RESULTS: Three different CAR intracellular regions CAR1 (CD244), CAR2 (CD244, NKG2D) and CAR3 (CD244, NKG2D, and CD3ζ) were constructed. CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells. Compared with anti-PSMA, p-PSMA exhibited enhanced affinity for the tumor antigen. Thus, p-PSMA-CAR-NK92MI cells, which expressed CAR with a polypeptide-based antigen-binding region, an intracellular CD244 and a NKG2D costimulatory domain, were generated. They could selectively and successfully kill PSMA+ target cells and exhibited specific lysis rate of 73.19% for PSMA-positive C4-2 cells and 33.04% for PSMA-negative PC3 cells. Additionally, p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ, TNF-α and granzyme B than NK92MI cells. In a CRPC cancer xenograft model, p-PSMA-CAR-NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells. Moreover, ferroptosis is a potential mechanism through which CAR-NK92MI cells attack cancer cells, and is triggered by IFN-γ. CONCLUSIONS: p-PSMA-CAR-NK92MI cells can effectively kill CRPCPSMA+ cells in vitro and in vivo. This strategy may provide additional treatment options for patients with CRPC.

Validation of CT-Based Three-Dimensional Preoperative Planning in Comparison with Acetate Templating for Primary Total Hip Arthroplasty.

OBJECTIVE: This study aims to compare the accuracy of CT-based preoperative planning with that of acetate templating in predicting implant size, neck length, and neck cut length, and to evaluate the reproducibility of the two methods. METHODS: This prospective study was conducted between August 2020 and March 2021. Patients who underwent elective primary total hip arthroplasty by a single surgeon were assessed for eligibility. The included patients underwent both acetate templating and CT-based planning by two observers after the operation. Each observer conducted both acetate templating and CT-based planning twice for each case. The outcome measures included the following: (1) the accuracy of surgical planning in predicting implant size, calcar length, and neck length, which was defined as the difference between the planned size and length and the actual size and length; (2) reproducibility of the two planning techniques, which were assessed by inter-observer and intra-observer reliability analysis; (3) the influence of potential confounding factors on planning accuracy, which was evaluated using generalized estimating equations. RESULTS: A total of 57 cases were included in the study. CT-based planning was more accurate than acetate templating for predicting cup size (93% vs 79%, p < 0.001) and stem size (93% vs 75%, p < 0.001). When assessed by mean absolute difference, the comparison between acetate templating and CT-based planning was 4.28 mm vs 3.74 mm (p = 0.122) in predicting neck length and 3.05 mm vs 2.93 mm (p = 0.731) in predicting neck cut length. In the inter-observer reliability analysis, an intraclass correlation coefficient (ICC) of 0.790 was achieved for predicting cup size, and an ICC of 0.966 was achieved for predicting stem size using CT-based planning. In terms of intra-observer reliability, Observer 1 achieved an ICC of 0.803 for predicting cup size and 0.965 for predicting stem size in CT-based planning. Observer 2 achieved ICC values of 0.727 and 0.959 for predicting cup and stem sizes, respectively. The average planning time was 6.48 ± 1.55 min for CT-based planning and 6.12 ± 1.40 min for acetate templating (p = 0.015). CONCLUSION: The CT-based planning system is more accurate than acetate templating for predicting implant size and has good reproducibility in total hip arthroplasty.

Deep learning-based multimodal image analysis for cervical cancer detection.

Cervical cancer is the fourth most common cancer in women, and its precise detection plays a critical role in disease treatment and prognosis prediction. Fluorodeoxyglucose positron emission tomography and computed tomography, i.e., FDG-PET/CT and PET/CT, have established roles with superior sensitivity and specificity in most cancer imaging applications. However, a typical FDG-PET/CT analysis involves the time-consuming process of interpreting hundreds of images, and the intense image screening work has greatly hindered clinicians. We propose a computer-aided deep learning-based framework to detect cervical cancer using multimodal medical images to increase the efficiency of clinical diagnosis. This framework has three components: image registration, multimodal image fusion, and lesion object detection. Compared to traditional approaches, our adaptive image fusion method fuses multimodal medical images. We discuss the performance of deep learning in each modality, and we conduct extensive experiments to compare the performance of different image fusion methods with some state-of-the-art (SOTA) object-detection deep learning-based methods in images with different modalities. Compared with PET, which has the highest recognition accuracy in single-modality images, the recognition accuracy of our proposed method on multiple object detection models is improved by an average of 6.06%. And compared with the best results of other multimodal fusion methods, our results have an average improvement of 8.9%.

Development and Validation of an Artificial Intelligence Preoperative Planning System for Total Hip Arthroplasty.

Background: Accurate preoperative planning is essential for successful total hip arthroplasty (THA). However, the requirements of time, manpower, and complex workflow for accurate planning have limited its application. This study aims to develop a comprehensive artificial intelligent preoperative planning system for THA (AIHIP) and validate its accuracy in clinical performance. Methods: Over 1.2 million CT images from 3,000 patients were included to develop an artificial intelligence preoperative planning system (AIHIP). Deep learning algorithms were developed to facilitate automatic image segmentation, image correction, recognition of preoperative deformities and postoperative simulations. A prospective study including 120 patients was conducted to validate the accuracy, clinical outcome and radiographic outcome. Results: The comprehensive workflow was integrated into the AIHIP software. Deep learning algorithms achieved an optimal Dice similarity coefficient (DSC) of 0.973 and loss of 0.012 at an average time of 1.86 ± 0.12 min for each case, compared with 185.40 ± 21.76 min for the manual workflow. In clinical validation, AIHIP was significantly more accurate than X-ray-based planning in predicting the component size with more high offset stems used. Conclusion: The use of AIHIP significantly reduced the time and manpower required to conduct detailed preoperative plans while being more accurate than traditional planning method. It has potential in assisting surgeons, especially beginners facing the fast-growing need for total hip arthroplasty with easy accessibility.

Comparative Analysis of Differentially Mutated Genes in Non-Muscle and Muscle-Invasive Bladder Cancer in the Chinese Population by Whole Exome Sequencing.

Objective: To characterize the spectra of mutations in non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) in the Chinese population to identify any mutational features and find potential therapeutic targets. Materials and methods: We collected fresh bladder tumor samples from NMIBC (n = 9) and MIBC patients (n = 11) along with adjacent normal bladder tissue specimen and peripheral blood sample. Using whole exome sequencing (WES), we analyzed the mutation spectra of those NMIBC and MIBC bladder cancer (BCa) specimen. Results: Our results demonstrated that 95% of BCa patients (19/20) had varying degrees of driver gene mutations, FGFR3 (45%), KMT2D (40%), PIK3CA (35%), ARID1A (20%), EP300 (20%), KDM6A (20%), KMT2C (20%), and STAG2 (20%) were the most frequently mutated genes in BCa patients. NMIBC and MIBC exhibited different genomic alterations. FGFR3 (67%), PIK3CA (56%), and RHOB (44%) were the most frequently mutated genes in NMIBC patients. Of note, RHOB mutation only occurred in NMIBC, whereas mutations of KMT2D (55%), TP53 (36%) and KMT2B (27%) were frequently detected in MIBC, and TP53 and KMT2B mutation only occurred in MIBC. The frequency of mutations in DNA-damage repair (DDR) gene was higher in MIBC than that in NMIBC (91 vs 78%, 6.2 vs 2.4 gene mutations per patient). Copy number alterations (CNAs) occurred at more diverse chromosomal locations in NMIBC, but the CNA burden was higher in MIBC [9.01 (2.07-31.51) vs 4.98 (0.99-9.73) mutations/Mb]., the trend of which was consistent with the tumor mutation burden (TMB) [8.26 (4.63-21.84) vs 5.58 (3.87-9.58) mutations/Mb]. Among the current set of single-base substitution (SBS) signatures including SBS 1, 2, 5, 13, and 40, we identified one differently expressed signature between NMIBC and MIBC patients: SBS13. Conclusions: There were different gene mutational characteristics and signatures between NMIBC and MIBC in the Chinese population. Frequency of DDR, CNA burden and TMB were higher in MIBC. Our analysis revealed that several genes in NMIBC did not overlap with those reported in MIBC, suggesting that a fraction of NMIBC and MIBC likely developed secondary to different precursor lesions.

Spatial variations on the hydrochemistry, controls, and solute sources of surface water in the Weihe River Basin, China.

The Weihe River Basin (WRB), the largest tributary of the Yellow River Basin (YRB), is located in the northwest of China. As the "mother river" of the Guanzhong Plain, it plays an important role in the development of Guanzhong City Group. Based on pH, electric conductivity (EC), total dissolved solids (TDS), and major ionic concentrations of 227 samples collected from the main stream (MS), northern tributaries (NT), and southern tributaries (ST) of the WRB, we explored spatial differential characteristics of hydrochemistry and their controlling factors, solute sources, and water quality of surface water. The results revealed mildly alkaline pH and much higher TDS values than the global average with mean values of 7.9 and 1037.7 mg L-1, respectively. Except NO3-, the concentrations of major ions in the MS and NT were higher than those of the ST, with similar spatial distribution patterns of Ca2+, Na+, Mg2+, SO42-, and Cl-. Na+ and SO42- were the most dominant cation and anion in the MS and NT controlled by both rock weathering and evaporation-crystallization processes. Ca2+ and HCO3- were the most dominant cation and anion in the ST mainly controlled by rock weathering process. Evaporite dissolution contributed the most to dissolved solutes in the MS and NT, while carbonate weathering dominated dissolved solutes in the ST. These findings were confirmed by the results of correlation matrix, principal component analysis (PCA), stoichiometric plots, and different water types identified as Na-SO4·Cl in the MS and NT, and Ca-HCO3 in the ST. Atmospheric and anthropogenic inputs had a minor effect on the surface water chemistry. However, human activities could not be ignored in the ST accounting for 10.9% of the total dissolved solutes, mainly because of the fertilizer application. And the surface water of the ST was more suitable for irrigation and drinking purposes than that of the MS and NT. Knowledge of our findings could contribute new insights to the solute geochemistry and sustainable management of water resources in the lithologically distinct segments of the WRB and other similar areas.

PhenoApt leverages clinical expertise to prioritize candidate genes via machine learning.

In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG ) mimicking hyperglycemia in patientEC+/dia+ . Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of IshikawaHG as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (miceEC+/dia+ ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+ . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+ .

Long-term observations of the chemical composition, fluxes and sources of atmospheric wet deposition at an urban site in Xi'an, Northwest China.

Atmospheric wet deposition (AWD) is closely related to air quality, and excessive deposition poses risks to ecological systems and human health. Seasonal and interannual variations in acidity, electric conductivity (EC), ionic composition, fluxes, sources, and atmospheric transport of AWD were analyzed at an urban site in Xi'an from 2016 to 2019. The annual volume-weighted mean (VWM) pH and EC values were 6.8 and 40.6 µS cm-1, respectively. NO3- (47%) was the most dominant anion, while Ca2+ (34%) was the most dominant cation. The analysis of fractional acidity (FA) and neutralization factors (NFs) showed that 96% of the acidity was neutralized by alkaline constituents, especially Ca2+ and NH4+. The annual AWD flux of total ions was 125.9 kg ha-1 year-1, and NO3-, NO2-, SO42- and NH4+ fluxes accounted for approximately 70%, indicating considerable sulfur (9.1 kg ha-1 year-1) and nitrogen (22.0 kg ha-1 year-1) deposition. Under dilution by precipitation, the EC and major ion concentrations were lower, while the pH and fluxes were higher, in summer and autumn, and the opposite results were observed in spring and winter. The source apportionment via by positive matrix factorization (PMF) revealed that the six sources of major ions were confirmed as follows: vehicular emissions (38.1%), agriculture (22.3%), fossil fuel combustion (13.8%), crust (12.9%), marine (9.6%), and biomass burning (3.3%). And on the basis of back trajectory analysis, the air masses of precipitation were primarily from the northwest in spring and winter, from the southeast in summer, and from various directions in autumn, and they transported different natural and anthropogenic pollutants along their paths, thereby affecting the chemical composition and fluxes of AWD.