Artificial intelligence enhances whole-slide interpretation of PD-L1 CPS in triple-negative breast cancer: A multi-institutional ring study.

BACKGROUND AND AIMS: Evaluation of the programmed cell death ligand-1 (PD-L1) combined positive score (CPS) is vital to predict the efficacy of the immunotherapy in triple-negative breast cancer (TNBC), but pathologists show substantial variability in the consistency and accuracy of the interpretation. It is of great importance to establish an objective and effective method which is highly repeatable. METHODS: We proposed a model in a deep learning-based framework, which at the patch level incorporated cell analysis and tissue region analysis, followed by the whole-slide level fusion of patch results. Three rounds of ring studies (RSs) were conducted. Twenty-one pathologists of different levels from four institutions evaluated the PD-L1 CPS in TNBC specimens as continuous scores by visual assessment and our artificial intelligence (AI)-assisted method. RESULTS: In the visual assessment, the interpretation results of PD-L1 (Dako 22C3) CPS by different levels of pathologists have significant differences and showed weak consistency. Using AI-assisted interpretation, there were no significant differences between all pathologists (P = 0.43), and the intraclass correlation coefficient (ICC) value was increased from 0.618 [95% confidence interval (CI) = 0.524-0.719] to 0.931 (95% CI = 0.902-0.955). The accuracy of interpretation result is further improved to 0.919 (95% CI = 0.886-0.947). Acceptance of AI results by junior pathologists was the highest among all levels, and 80% of the AI results were accepted overall. CONCLUSION: With the help of the AI-assisted diagnostic method, different levels of pathologists achieved excellent consistency and repeatability in the interpretation of PD-L1 (Dako 22C3) CPS. Our AI-assisted diagnostic approach was proved to strengthen the consistency and repeatability in clinical practice.

A nursing report on a corneal contact lens wearer receiving keratoplasty due to corneal ulcer and perforation caused by Pythium insidiosum infection: A case report.

BACKGROUND: To report the nursing experience of a case of corneal contact lens wearer receiving the 2nd keratoplasty due to corneal ulcer and perforation caused by Pythium insidiosum infection. METHODS: A 30-year-old female patient had blurred vision after deep anterior lamellar keratoplasty for a right corneal ulcer. At the 5th week, the right eye appeared the symptoms, such as redness and pain. The anterior segment photography was performed on the eye, and the result showed that the epithelium was missing in the right eye lesion area, and a large number of longitudinal and transversal streaks were visible from the epithelium to the stroma, with fungus filaments to be discharged. Upon macro-genome sequencing of the corneal secretion, a P. insidiosum infection was observed. Then, the patient underwent the keratoplasty, and 3 weeks later, the corneal implant showed a tendency to dissolve, the sutures were partially loosened, and the eye was almost blind. Subsequently, the patient was admitted to our hospital and subject to the 2nd penetrating keratoplasty of the right eye (allograft). After surgery, linezolid and azithromycin injections were given through intravenous drip and local drip of the eye for anti-inflammation, and tacrolimus eye drops for antirejection. RESULTS: Postoperatively, the patient showed signs of recovery with slight corneal edema and visible pupil, leading to discharge with improved vision. The corneal implant was normal 1 week after surgery and the vision of the right eye was hand move/before eye at the 6th month of follow-up. Continuous care and removal of sutures 3 months post-surgery contributed to a successful outcome, with the patient achieving hand motion vision 6 months after the procedure. CONCLUSION: Corneal ulcer caused by P. insidiosum infection not only needs timely and effective keratoplasty intervention, but also requires perfect nursing measures.

Serum and urine metabolomics based on UPLC-QTOF/MS reveal the effect and potential mechanism of "schisandra-evodia" herb pair in the treatment of Alzheimer's disease.

The "schisandra-evodia" herb pair (S-E) is a herbal preparation to treat Alzheimer's disease (AD). This study aims to investigate the therapeutic efficacy and potential mechanism of S-E in AD rats, utilizing pharmacodynamic assessments and serum- and urine-based metabolomic analyses. Pharmacodynamic assessments included Morris water maze test, hematoxylin-eosin staining and immunohistochemistry experiments. The results of the study showed that the AD model was successful; the S-E significantly enhanced long-term memory and spatial learning in AD rats. Meanwhile, S-E notably ameliorated Aß25-35-induced cognitive impairment, improved hippocampal neuron morphology, decreased Aß deposition in the hippocampus and mitigated inflammatory damage. We then analyzed serum and urine samples using UPLC-MS/MS to identify potential biomarkers and metabolic pathways. Metabolomic analysis revealed alterations in 40 serum metabolites and 38 urine metabolites following S-E treatment, predominantly affecting pathways related to taurine and hypotaurine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism and arachidonic acid metabolism. This study elucidates the biochemical mechanism underlying AD and the metabolic pathway influenced by S-E, laying the groundwork for future clinical applications.

Direct conversion of methane to aromatics and hydrogen via a heterogeneous trimetallic synergistic catalyst.

Non-oxidative methane dehydro-aromatization reaction can co-produce hydrogen and benzene effectively on a molybdenum-zeolite based thermochemical catalyst, which is a very promising approach for natural-gas upgrading. However, the low methane conversion and aromatics selectivity and weak durability restrain the realistic application for industry. Here, a mechanism for enhancing catalysis activity on methane activation and carbon-carbon bond coupling has been found to promote conversion and selectivity simultaneously by adding platinum-bismuth alloy cluster to form a trimetallic catalyst on zeolite (Pt-Bi/Mo/ZSM-5). This bimetallic alloy cluster has synergistic interaction with molybdenum: the formed CH3* from Mo2C on the external surface of zeolite can efficiently move on for C-C coupling on the surface of Pt-Bi particle to produce C2 compounds, which are the key intermediates of oligomerization. This pathway is parallel with the catalysis on Mo inside the cage. This catalyst demonstrated 18.7% methane conversion and 69.4% benzene selectivity at 710 °C. With 95% methane/5% nitrogen feedstock, it exhibited robust stability with slow deactivation rate of 9.3% after 2 h and instant recovery of 98.6% activity after regeneration in hydrogen. The enhanced catalytic activity is strongly associated with synergistic interaction with Mo and ligand effects of alloys by extensive mechanism studies and DFT calculation.

LncRNA Meg3 Aggravates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Rats by Activating the Hedgehog Pathway.

BACKGROUND: The hedgehog signaling pathway exerts vital functions in regulating epithelial-to-mesenchymal transition (EMT) in renal interstitial fibrosis (RIF). It was reported that lncRNA-maternally expressed gene 3 (lncRNA Meg3) can regulate hepatic fibrosis by regulating the expression of smoothened (Smo) in the hedgehog signaling pathway. However, the specific role of lncRNA Meg3 in renal fibrosis resulting from unilateral ureteral obstruction (UUO) by regulating the hedgehog signaling pathway has not been reported. Hence, this research aimed to expound the effects of lncRNA Meg3 on renal fibrosis induced by UUO in rats via the hedgehog pathway. METHODS: Peripheral blood was collected from patients with chronic kidney disease (CKD, CKD group) and healthy volunteers (Normal group) at the same period. In addition, 6-week-old male Sprague-Dawley (SD) rats were divided to Sham, UUO, UUO+shRNA Negative control (shNC), and UUO+sh-Meg3 groups, and their kidney tissues and serum were gathered. Next, quantitative real-time polymerase chain reaction (qRT-PCR) was employed for detecting the lncRNA Meg3 expression level in the serum of patients and renal tissue of rats; kits for testing levels of blood urea nitrogen (BUN), creatinine (Cr), hydroxyproline (HYP), and 24-hour urine protein (24-up) in rats of each group; hematoxylin and eosin (HE) staining and Masson staining for observing kidney tissue and renal fibrosis level in rats; western blot for measuring levels of collagen type III (Col III), α-Smooth muscle actin (α-SMA), fibronectin, E-cadherin, sonic hedgehog (Shh), patched (Ptch) protein, smoothened (Smo) protein and glioma-associated oncogene homolog 1 (Gli1) protein expression. RESULTS: LncRNA Meg3 was highly expressed in CKD patients and UUO rats (p < 0.01). In contrast to the UUO+shNC group, knocking down lncRNA Meg3 improved renal injury, relieved pathological renal lesions, and reduced kidney fibrosis and related protein levels. It inhibited the hedgehog pathway in kidney tissues of UUO rats (p < 0.05 and p < 0.01). CONCLUSIONS: LncRNA Meg3 can aggravate UUO-induced rat renal fibrosis by activating the hedgehog pathway.

Bacillus licheniformis ameliorates Aflatoxin B1-induced testicular damage by improving the gut-metabolism-testis axis.

Global aflatoxin B1 (AFB1) contamination is inevitable, and it can significantly damage testicular development. However, the current mechanism is confusing. Here, by integrating the transcriptome, microbiome, and serum metabolome, we comprehensively explain the impact of AFB1 on testis from the gut-metabolism-testis axis. Transcriptome analysis suggested that AFB1 exposure directly causes abnormalities in testicular inflammation-related signalling, such as tumor necrosis factor (TNF) pathway, and proliferation-related signalling pathways, such as phosphatidylinositide 3-kinases-protein kinase B (PI3K-AKT) pathway, which was verified by immunofluorescence. On the other hand, we found that upregulated inflammatory factors in the intestine after AFB1 exposure were associated with intestinal microbial dysbiosis, especially the enrichment of Bacilli, and enrichment analysis showed that this may be related to NLR family pyrin domain containing 3 (NLRP3)-mediated NOD-like receptor signalling. Also, AFB1 exposure caused blood metabolic disturbances, manifested as decreased hormone levels and increased oxidative stress. Significantly, B. licheniformis has remarkable AFB1 degradation efficiency (> 90%). B. licheniformis treatment is effective in attenuating gut-testis axis damage caused by AFB1 exposure through the above-mentioned signalling pathways. In conclusion, our findings indicate that AFB1 exposure disrupts testicular development through the gut-metabolism-testis axis, and B. licheniformis can effectively degrade AFB1.

Improvement of Cancer Prevention and Control: Reflection on the Role of Emerging Information Technologies.

Cancer has become an important public health problem affecting the health of Chinese residents, as well as residents all over the world. With the improvement of cancer prevention and treatment, the growth of the mortality rate of cancers has slowed down gradually, but the incidence rate is still increasing rapidly, and cancers still impose heavy disease and economic burdens. Cancer screening and early cancer diagnosis and treatment are important ways to reduce the burden of cancer-related diseases. At present, various projects for early cancer diagnosis and treatment have been implemented in China. With the expansion of the coverage of these projects, the problems related to project implementation, operation, and management have emerged gradually. In recent years, emerging information technologies have been applied in the field of health and have facilitated health management and clinical decision-making. Meanwhile, China announced multiple policies to encourage and promote the application of information technologies in the field of health. Therefore, combined with the analysis of major problems in cancer prevention and control projects, this paper probes into how to apply information technologies such as biological information mining, artificial intelligence, and electronic information collection technology to various stages of cancer prevention and control. Information technologies realize the integrated management of prevention and control processes, for example, mobilization and preliminary identification, high-risk assessment, clinical screening, clinical diagnosis and treatment, tracking and follow-up, and biological sample management of high-risk groups, and promote the efficient implementation of cancer prevention and control projects in China.

Covalently-Bonded Laminar Assembly of Van der Waals Semiconductors with Polymers: Toward High-Performance Flexible Devices.

Van der Waals semiconductors (vdWS) offer superior mechanical and electrical properties and are promising for flexible microelectronics when combined with polymer substrates. However, the self-passivated vdWS surfaces and their weak adhesion to polymers tend to cause interfacial sliding and wrinkling, and thus, are still challenging the reliability of vdWS-based flexible devices. Here, an effective covalent vdWS-polymer lamination method with high stretch tolerance and excellent electronic performance is reported. Using molybdenum disulfide (MoS2 )and polydimethylsiloxane (PDMS) as a case study, gold-chalcogen bonding and mercapto silane bridges are leveraged. The resulting composite structures exhibit more uniform and stronger interfacial adhesion. This enhanced coupling also enables the observation of a theoretically predicted tension-induced band structure transition in MoS2 . Moreover, no obvious degradation in the devices' structural and electrical properties is identified after numerous mechanical cycle tests. This high-quality lamination enhances the reliability of vdWS-based flexible microelectronics, accelerating their practical applications in biomedical research and consumer electronics.

A model based on immunogenic cell death-related genes predicts prognosis and response to immunotherapy in kidney renal clear cell carcinoma.

Background: The prognosis of patients with kidney renal clear cell carcinoma (KIRC), a life-threatening condition, is poor. Immunogenic cell death (ICD) induces regulated cell death via immunogenic signal secretion and exposure. ICD induces regulated cell death through immunogenic signal secretion and exposure. ICD plays an essential role in tumorigenesis, however, the role of ICD in KIRC remains unclear. Methods: This study examined the expression levels of 34 ICD-related genes in The Cancer Genome Atlas (TCGA) data set. Signature genes linked to KIRC survival were identified using Cox regression. Next, a prognostic risk model (RM) was built. Subsequently, the KIRC patients were divided into low- and high-risk groups. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were plotted. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were carried out to investigate the possible role of differential gene expression between the two groups. The immune microenvironment (IME) was assessed using Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression, CIBERSORT, and single-sample gene-set enrichment analysis algorithms. An enrichment analysis was used to determine the biological significance of these regulatory networks we conducted. The relationship between immune checkpoint gene expression and risk score, and the relationship between treatment outcome and gene expression were assessed using correlation analyses. Results: We developed a KIRC RM based on five ICD-related genes (i.e., FOXP3, IFNB1, IL6, LY96, and TLR4), which were identified as the prognostic signature genes. Using the TCGA data set, we conducted a survival analysis and found that the 3-year RM had an area under the curve (AUC) of 0.735, which validated the reliability of the signature. Similarly, using the International Cancer Genome Consortium (ICGC) data set, we found that the 3-year RM had an AUC of 0.732. Conclusions: A RM based on five ICD-related genes was built to predict the prognosis of KIRC patients. This RM predicted patient prognosis and reflected the tumor IME of KIRC patients. Thus, this RM could be used to promote individualized treatments and provide potential novel targets for immunotherapy.

A novel ratiometric fluorescence probe based on the FRET-ICT mechanism for detecting fluoride ions and viscosity.

Fluoride ion is not only important for dental health, but also a contributing factor in a variety of diseases. At the same time, fluoride ions and cell viscosity are both important to the physiological environment of mitochondria. We developed a dual-response ratiometric fluorescent probe BDF based on Förster resonance energy transfer (FRET) and intramolecular charge transfer (ICT) mechanism for the detection of F- and viscosity. BDF has an outstanding intramolecular energy transfer efficiency of 97.7% and shows excellent performance for fluorine ion detection. In addition, when the system viscosity increases, the fluorescence emission intensity of BDF is greatly heightened, indicating the possibility of viscosity detection. Finally, based on the fluorescence properties of BDF, we used the probe to detect F- in the toothpaste sample and image exogenous fluoride ions in HeLa cells.

Safety and Efficacy of Second-Line TKI Plus Anti-PD1 in Metastatic Non-Clear Cell Renal Cell Carcinoma: A Real-World Study.

OBJECTIVES: Guidelines recommend clinical trials or tyrosine kinase inhibitor (TKI) as the first-line option for systemic therapy for non-clear cell renal cell carcinoma (nccRCC) with limited efficacy. However, the preferred subsequent options remain unclear when patients progress after first-line treatment. This study aimed to evaluate the efficacy and safety of anti-PD-1 plus TKI therapy as the second-line regimen in nccRCC. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020. The baseline characteristics of the patients and adverse events (AEs) were collected. Efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). RESULTS: The current study enrolled 65 patients, with a median age of 48 (interquartile 37-60) years. Among all patients, 21 received TKI monotherapy while 44 patients received combination therapy (TKI plus anti-PD1). The ORR and DCR for the whole cohort were 38.5% and 56.9%, respectively. ORR (50.0% vs. 14.3%, P = .006) and DCR (70.5% vs. 28.6%, P = .001) were improved in the combination group compared with the TKI group. The overall second-line PFS was 7.7 (95% CI: 6.1-9.3) months and OS was 25.2 (19.5-30.8) months. Patients receiving combination therapy had a longer PFS compared with those receiving TKI monotherapy [median PFS (95% CI): 9.2 (5.9-12.4) vs. 5.4 (2.6-8.2) m, Log-rank P = .002]. The incidence of treatment-related AEs of grade 3 or higher was comparable between the 2 groups (56.8% vs. 52.4%). CONCLUSION: Anti-PD-1 plus TKI therapy appeared effective and safe in the treatment of patients with metastatic nccRCC who progressed after first-line TKIs.

Longitudinal changes in renal parenchymal volume and function status after partial nephrectomy: a retrospective cohort study.

BACKGROUND: The ipsilateral renal parenchymal volume (RPV) experiences a sharp decrease shortly after partial nephrectomy (PN), mainly due to surgical remove or devascularization of kidney tissue. However, the subsequent change of RPV and its association with glomerular filtration rate (GFR) fast decline remains unknown. Our objective was to investigate the change of ipsilateral RPV and renal function status from new baseline (1-12 months after PN) to latest follow-up (≥1 year) after PN, and to explore factors associated with ipsilateral RPV decrease rate and correlation between RPV decrease and GFR fast decline. MATERIALS AND METHODS: A retrospective review of 367 patients with PN was conducted. Three-dimensional reconstruction of computed tomography (CT)/MRI images was performed for RPV calculation. Spectrum score was used to assess the degree of acute kidney injury (AKI) in the operated kidney after PN. GFR decline greater than 3 ml/min/1.73 m 2 /year was defined as GFR fast decline. One hundred fourteen patients underwent abdominal surgery was used as control. Predictive factors for subsequent decrease of RPV rate and GFR fast decline were evaluated by linear and logistic regression, respectively. RESULTS: With a median interval time of 21.1 (interquartile range:13.8-35.5) months, median ipsilateral RPV significantly decreased from 118.7 (interquartile range:100.7-137.1) ml at new baseline to 111.8 (IQR: 92.3-131.3) ml at latest follow-up. The interval time [ß: 1.36(0.71-2.01), P <0.001] and spectrum score [ß: 5.83 (2.92-8.74), P <0.001] were identified as independent predictors of ipsilateral RPV decrease rate. GFR fast decline was observed in 101 (27.5%) patients. Annual ipsilateral RPV decrease rate [odds ratio:1.67 (1.05-2.67), P =0.03] and overweight [odds ratio:1.63 (1.02-2.60), P =0.04] were independent predictors of GFR fast decline. CONCLUSIONS: Ipsilateral RPV experienced a moderate but significant decrease during follow-up after PN, especially in those with severer acute kidney injury. The presence of GFR fast decline was found to be associated with reduction of ipsilateral RPV, particularly in overweight individuals.

Rejoint of Carbon Nitride Fragments into Multi-Interfacial Order-Disorder Homojunction for Robust Photo-Driven Generation of H2 O2.

Photocatalytic technology based on carbon nitride (C3 N4 ) offers a sustainable and clean approach for hydrogen peroxide (H2 O2 ) production, but the yield is severely limited by the sluggish hot carriers due to the weak internal electric field. In this study, a novel approach is devised by fragmenting bulk C3 N4  into smaller pieces (CN-NH4 ) and then subjecting it to a directed healing process to create multiple order-disorder interfaces (CN-NH4 -NaK). The resulting junctions in CN-NH4 -NaK significantly boost charge dynamics and facilitate more spatially and orderly separated redox centers. As a result, CN-NH4 -NaK demonstrates outstanding photosynthesis of H2 O2 via both two-step single-electron and one-step double-electron oxygen reduction pathways, achieving a remarkable yield of 16675 µmol h-1  g-1 , excellent selectivity (> 91%), and a prominent solar-to-chemical conversion efficiency exceeding 2.3%. These remarkable results surpass pristine C3 N4 by 158 times and outperform previously reported C3 N4 -based photocatalysts. This work represents a significant advancement in catalyst design and modification technology, inspiring the development of more efficient metal-free photocatalysts for the synthesis of highly valued fuels.

In situ generated iron oxide nanosheet on iron foam electrode for enhanced electro-Fenton performance toward pharmaceutical wastewater treatment.

Electro-Fenton (EF) is considered to be an effective technology for the purification of organic wastewater containing antibiotics, but the construction of accessible and efficient heterogeneous EF catalytic materials still faces challenges. In this study, an iron foam-derived electrode (FeOx/if-400) was prepared by a simple method (chemical oxidation combined heat treatment). The fabricated electrode presented great EF degradation efficiency under wide pH range (almost completely removing 50 mg L-1 TNZ within 60 min) and maintained great stability after consecutive operation (>95% removal after six cycles). Also, the FeOx/if-400 electrode showed good purification ability for pharmaceutical wastewater as evaluated by the quadrupole time-of-flight mass spectrometry and the three-dimensional excitation-emission matrix fluorescence spectroscopy. Based on experimental results, characterization analysis, and density functional theory (DFT) calculations, the EF reaction mechanism of FeOx/if-400 electrode and the organics degradation pathways in simulated and real matrices were proposed. Significantly, the biotoxicity assessment of the degradation intermediate products was revealed by ECOSAR software and relative inhibition of E. coli, which fully proved the environmental friendliness of the EF process by the FeOx/if-400 cathode. This work provides a green and effective EF system, showing a promising application potential in the field of organic wastewater treatment containing antibiotic contaminants.

Extraperitonealization of the ileal conduit decreases the risk of parastomal hernia: A single-center, randomized clinical trial.

Parastomal hernia (PSH) is a common complication in patients receiving ileal conduit urinary diversion after radical cystectomy. In this randomized controlled clinical trial, we validate our previous finding that extraperitonealization of ileal conduit decreases incidence of PSH. In total, 104 consecutive patients undergoing radical cystectomy at Sun Yat-sen University Cancer Center are randomized 1:1 to receive either modified (extraperitonealized) ileal conduit (n = 52) or conventional ileal conduit (n = 52). Primary endpoint is incidence of radiological PSH during follow-up. Incidence of radiological PSH is lower in the modified group than in the conventional group (11.5% vs. 28.8%; p = 0.028) after a median follow-up of 32 months, corresponding to a hazard ratio of 0.374 (95% confidence interval: 0.145-0.965, p = 0.034) in the modified conduit group. The results support our previous finding that extraperitonealization of the ileal conduit is effective for reducing risk of PSH in patients receiving ileal conduit diversion.

CXCL14 as a potential marker for immunotherapy response prediction in renal cell carcinoma.

Background: Epigenetic mechanisms play vital roles in the activation, differentiation, and effector function of immune cells. The breast and kidney-expressed chemokine (CXCL14) mainly contributes to the regulation of immune cells. However, its role in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in renal cell carcinoma (RCC). Objectives: This study aimed to elucidate the role of CXCL14 in predicting the efficacy of immunotherapy in patients with RCC. Methods: CXCL14 expression and RNA-sequencing, single-cell RNA-sequencing (scRNA-seq), and survival datasets of RCC from public databases were analyzed, and survival was compared between different CXCL14 levels. The correlation between CXCL14 and immune infiltration and human leukocyte antigen (HLA) gene expression was analyzed with TIMER2.0 and gene expression profiling interactive analysis. Institutional scRNA-seq and immunohistochemical staining analyses were used to verify the relationship between CXCL14 expression level and the efficacy of immunotherapy. Results: CXCL14 was expressed in fibroblast and malignant cells in RCC, and higher expression was associated with better survival. Enrichment analysis revealed that CXCL14 is involved in immune activation, primarily in antigen procession, antigen presentation, and major histocompatibility complex assemble. CXCL14 expression was positively correlated with T-cell infiltration as well as HLA-related gene expression. Among the RCC cohort receiving nivolumab in Checkmate 025, the patients with CXCL14 high expression had better overall survival than those with CXCL14 low expression after immunotherapy. scRNA-seq revealed a cluster of CXCL14+ fibroblast in immunotherapy responders. Immunohistochemistry analysis verified that the patients with high CXCL14 expression had an increased proportion of high CD8 expression simultaneously. The expression level of CXCL14 was associated with CXCR4 expression in RCC. Conclusion: CXCL14 expression is associated with immunotherapy response in RCC. It is a promising biomarker for immunotherapy response prediction and may be an effective epigenetic modulator in combination with immunotherapy approaches.

CXCL14 as potential predictor for immunotherapy response in kidney cancer Kidney-expressed chemokine (CXCL14) regulates immune cells. We studied how it affects the body's immune response to kidney cancer based on public and private database and staining. We found that higher levels of CXCL14 in kidney cancer were linked to better patient survival. CXCL14 seems to help activate the immune system. When patients with high CXCL14 levels received immunotherapy, they tended to survive longer than those with low levels. Fibroblasts with CXCL14 were present in patients responding to immunotherapy. Further tests confirmed that high CXCL14 levels were related to more immune cells. CXCR4 may be its receptor in kidney cancer. This suggests that measuring CXCL14 levels could help predict how well a patient might respond to immunotherapy for kidney cancer.

Deep learning model for measuring the sagittal Cobb angle on cervical spine computed tomography.

PURPOSES: To develop a deep learning (DL) model to measure the sagittal Cobb angle of the cervical spine on computed tomography (CT). MATERIALS AND METHODS: Two VB-Net-based DL models for cervical vertebra segmentation and key-point detection were developed. Four-points and line-fitting methods were used to calculate the sagittal Cobb angle automatically. The average value of the sagittal Cobb angle was manually measured by two doctors as the reference standard. The percentage of correct key points (PCK), matched samples t test, intraclass correlation coefficient (ICC), Pearson correlation coefficient, mean absolute error (MAE), and Bland‒Altman plots were used to evaluate the performance of the DL model and the robustness and generalization of the model on the external test set. RESULTS: A total of 991 patients were included in the internal data set, and 112 patients were included in the external data set. The PCK of the DL model ranged from 78 to 100% in the test set. The four-points method, line-fitting method, and reference standard measured sagittal Cobb angles were - 1.10 ± 18.29°, 0.30 ± 13.36°, and 0.50 ± 12.83° in the internal test set and 4.55 ± 20.01°, 3.66 ± 18.55°, and 1.83 ± 12.02° in the external test set, respectively. The sagittal Cobb angle calculated by the four-points method and the line-fitting method maintained high consistency with the reference standard (internal test set: ICC = 0.75 and 0.97; r = 0.64 and 0.94; MAE = 5.42° and 3.23°, respectively; external test set: ICC = 0.74 and 0.80, r = 0.66 and 0.974, MAE = 5.25° and 4.68°, respectively). CONCLUSIONS: The DL model can accurately measure the sagittal Cobb angle of the cervical spine on CT. The line-fitting method shows a higher consistency with the doctors and a minor average absolute error.

Gemcitabine/nab-paclitaxel vs gemcitabine/carboplatin for advanced urothelial carcinoma.

OBJECTIVE: To compare in a phase III trial the efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine (GA) with that of carboplatin plus gemcitabine (GCb) as a first-line treatment for patients with cisplatin-ineligible metastatic urothelial cancer (mUC). PATIENTS AND METHODS: Treatment-naive, cisplatin-ineligible patients with mUC were assigned randomly to either the GA (both nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days) or GCb group (carboplatin area under the free carboplatin plasma concentration versus time curve of 4.5 on Day 1, gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety, and patient-reported outcomes (PROs). RESULTS: The trial was terminated early because of slow accrual after 54 patients were enrolled: 26 in in the GA group and 28 in the GCb groups. The median PFS was 6.7 vs 5.9 months for the GA and GCb groups, respectively (P = 0.248). The median OS time was 12.1 vs 10.7 months for the GA and GCb groups, respectively (P = 0.837). The ORR and DCR were 40% vs 46.4% (P = 0.637) and 72% vs 68% (P = 0.188) in the GA and GCb groups, respectively. Patients treated with GA showed significantly lower incidence of Grade 3-4 thrombocytopenia and does reduction and delay. Although peripheral sensory neuropathy was higher in the GA arm, no Grade 3 neuropathy occurred. There was no difference in the PROs between the two groups. CONCLUSION: While not powered for comparison, first-line GA showed similar efficacy and better tolerability and might be considered a rational alternative to GCb.

Diversity and evolution of the MHC class II DRB gene in the Capra sibirica experienced a demographic fluctuation in China.

The major histocompatibility complex (MHC) genes are the most polymorphic genes in vertebrates, and their proteins play a critical role in adaptive immunity for defense against a variety of pathogens. MHC diversity was lost in many species after experiencing a decline in size. To understand the variation and evolution of MHC genes in the Siberian ibex, Capra sibirica, which has undergone a population decline, we analyzed the variation of the second exon of MHC class II DRB genes in samples collected from five geographic localities in Xinjiang, China, that belong to three diverged mitochondrial clades. Consequently, we identified a total of 26 putative functional alleles (PFAs) with 260 bp in length from 43 individuals, and found one (for 27 individuals) to three (for 5 individuals) PFAs per individual, indicating the presence of one or two DRB loci per haploid genome. The Casi-DRB1*16 was the most frequently occurring PFA, Casi-DRB1*22 was found in only seven individuals, 14 PFAs occurred once, 7 PFAs twice, implying high frequency of rare PFAs. Interestingly, more than half (15) of the PFAs were specific to clade I, only two and three PFAs were specific to clades II and III, respectively. So, we assume that the polygamy and sexual segregation nature of this species likely contributed to the allelic diversity of DRB genes. Genetic diversity indices showed that PFAs of clade II were lower in nucleotide, amino acid, and supertype diversity compared to those of the other two clades. The pattern of allele sharing and FST values between the three clades was to some extent in agreement with the pattern observed in mitochondrial DNA divergence. In addition, recombination analyses revealed no evidence for significant signatures of recombination events. Alleles shared by clades III and the other two clades diverged 6 million years ago, and systematic neighbor grids showed Trans-species polymorphism. Together with the PAML and MEME analyses, the results indicated that the DRB gene in C. sibirica evolved under balancing and positive selection. However, by comparison, it can be clearly seen that different populations were under different selective pressures. Our results are valuable in understanding the diversity and evolution of the DRB gene in a mountain living C. sibirica and in making decisions on future long-term protection strategies.

[Analysis of medium and long term efficacy of ossicle chain bypass technique in treatment of tympanosclerosis].

Objective:For tympanosclerosis patients with ossicular chain fixation, we use ossicular chain bypass technique and evaluate its long-term effects. Methods:From June 2017 to June 2019, 147 patients with tympanosclerosis who underwent middle ear surgery with otoscopy in Yinchuan First People's Hospital were reviewed. The subjects were divided into three groups according to the implemented operation plan, 51 cases in the ossicular chain mobilization group（OCM）, 56 cases in the ossicular chain bypass reconstruction group（OCB）, and 40 cases in the malleus-incus complex resection reconstruction group（MICR）. Through a three-year follow-up, the medium and long-term effects of different operation plans were compared and analyzed. Results:There was no significant difference among the three groups in the incidence of tympanic membrane perforation, delayed facial nerve palsy, and the dispatch and displacement of PORP. The incidence of tympanic membrane retraction pocket or cholesteatoma after operation in OCB group（0） was significantly lower than that in OCM group（11.76%） and MICR group（7.5%）（P<0.05）. At 12 months after operation, ΔABG of OCB group and MICR group were better than that in the OCM group（P<0.05）. At 36 months after operation, ΔABG of OCB group was better than that in the OCM group（P<0.05）, and there was no significant difference between OCB group and MICR group. The audiological performance of patients with epitympanic sclerosis（ETS） at 12, 24 and 36 months after operation was better than that of patients with posterior tympanosclerosis（PTS） and total tympanosclerosis（TTS）（P<0.05）. Conclusion:Compared with patients undergoing ossicular chain mobilization and malleus-incus complex resection for ossicular chain reconstruction, patients with tympanosclerosis undergoing bypass technique have better and stable hearing prognosis in medium and long term. This technique can effectively prevent the formation of retracted pocket and cholesteatoma in patients with tympanosclerosis after operation.