High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease, PD); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small proluminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT-GBA1 transgene into an intragenic safe-harbor locus in GBA1-knockout H4 (neuroglioma) cells. This GD cell model was amenable to lead discovery via titration-based quantitative high-throughput screening and lead optimization via structure-activity relationships. A primary screen of 10,779 compounds from the NCATS bioactive collections identified 140 stabilizers of HiBiT-GCase-L444P, including both pharmacological chaperones (ambroxol and noninhibitory chaperone NCGC326) and proteostasis regulators (panobinostat, trans-ISRIB, and pladienolide B). Two complementary high-content imaging-based assays were deployed to triage hits: The fluorescence-quenched substrate LysoFix-GBA captured functional lysosomal GCase activity, while an immunofluorescence assay featuring antibody hGCase-1/23 directly visualized GCase lysosomal translocation. NCGC326 was active in both secondary assays and completely reversed pathological glucosylsphingosine accumulation. Finally, we tested the concept of combination therapy by demonstrating synergistic actions of NCGC326 with proteostasis regulators in enhancing GCase-L444P levels. Looking forward, these physiologically relevant assays can facilitate the identification, pharmacological validation, and medicinal chemistry optimization of small molecules targeting GCase, ultimately leading to a viable therapeutic for GD and PD.

Photonic Generation of Arbitrary Microwave Waveforms with Anti-Dispersion Transmission Capability.

We propose and demonstrate a photonic-assisted approach for generating arbitrary microwave waveforms based on a dual-polarization dual-parallel Mach-Zehnder modulator, offering significant advantages in terms of tunability of repetition rates and anti-dispersion capability. In order to generate diverse microwave waveforms, two sinusoidal radio frequency signals with distinct frequency relationships are applied to the dual-polarization dual-parallel Mach-Zehnder modulator. By adjusting the power of the applied sinusoidal radio frequency signal, the power ratio between these orthogonal polarized optical sidebands can be changed, and thereby desired radio frequency waveforms can be obtained after photoelectric conversion. In our proof-of-concept experiment, we systematically varied the repetition rate of triangular, rectangular and sawtooth waveforms. Meanwhile, we calculated the Root Mean Square Error (RMSE) to assess the approximation error in each waveform. The RMSEs are 0.1089, 0.2182 and 0.1185 for the triangular, rectangular and sawtooth microwave waveforms with repetition rate of 8 GHz, respectively. Furthermore, after passing through 25 km single mode fiber, the optical power decreased by approximately 5.6 dB, which verifies the anti-dispersion transmission capability of our signal generator.

Serum metabolomics analysis of malnutrition in patients with gastric cancer: a cross sectional study.

BACKGROUND: Although malnutrition is common in cancer patients, its molecular mechanisms has not been fully clarified. This study aims to identify significantly differential metabolites, match the corresponding metabolic pathways, and develop a predictive model of malnutrition in patients with gastric cancer. METHODS: In this cross-sectional study, we applied non-targeted metabolomics using liquid chromatography-mass spectrometry to explore the serum fingerprinting of malnutrition in patients with gastric cancer. Malnutrition-specific differential metabolites were identified by orthogonal partial least-squares discriminant analysis and t-test and matched with the Human Metabolome Database and the LIPID Metabolites and Pathways Strategy. We matched the corresponding metabolic pathways of malnutrition using pathway analysis at the MetaboAnalyst 5.0. We used random forest analyses to establish the predictive model. RESULTS: We recruited 220 malnourished and 198 non-malnourished patients with gastric cancer. The intensities of 25 annotated significantly differential metabolites were lower in patients with malnutrition than those without, while two others were higher in patients with malnutrition than those without, including newly identified significantly differential metabolites such as indoleacrylic acid and lysophosphatidylcholine(18:3/0:0). We matched eight metabolic pathways associated with malnutrition, including aminoacyl-tRNA biosynthesis, tryptophan metabolism, and glycerophospholipid metabolism. We established a predictive model with an area under the curve of 0.702 (95% CI: 0.651-0.768) based on four annotated significantly differential metabolites, namely indoleacrylic acid, lysophosphatidylcholine(18:3/0:0), L-tryptophan, and lysophosphatidylcholine(20:3/0:0). CONCLUSIONS: We identified 27 specific differential metabolites of malnutrition in malnourished compared to non-malnourished patients with gastric cancer. We also matched eight corresponding metabolic pathways and developed a predictive model. These findings provide supportive data to better understand molecular mechanisms of malnutrition in patients with gastric cancer and new strategies for the prediction, diagnosis, prevention, and treatment for those malnourished.

Medical and work loss costs of violence, self-harm, unintentional and traumatic brain injuries per injured person in the USA.

OBJECTIVE: Injuries and poisoning are leading causes of US morbidity and mortality. This study aimed to update medical and work loss cost estimates per injured person. METHODS: Injuries treated in emergency departments (ED) during 2019-2020 were analysed in terms of mechanism (eg, fall) and intent (eg, unintentional), as well as traumatic brain injury (TBI) (multiple mechanisms and intents). Fatal injury medical spending was based on the Nationwide Emergency Department Sample and National Inpatient Sample. Non-fatal injury medical spending and workplace absences (general, short-term disability and workers' compensation) were analysed among injury patients with commercial insurance or Medicaid and matched controls during the year following an injury ED visit using MarketScan databases. RESULTS: Medical spending for injury deaths in hospital EDs and inpatient settings averaged US$4777 (n=57 296) and US$45 678 per fatality (n=89 175) (2020 USD). Estimates for fatal TBI were US$5052 (n=5363) and US$47 952 (n=37 184). People with ED treat and release visits for non-fatal injuries had on average US$5798 (n=895 918) in attributable medical spending and US$1686 (11 missed days) (n=116 836) in work loss costs during the following year, while people with non-fatal injuries who required hospitalisation after an ED injury visit had US$52 246 (n=32 976) in medical spending and US$7815 (51 days) (n=4473) in work loss costs. Estimates for non-fatal TBI were US$4529 (n=25 792), US$1503 (10 days) (n=1631), US$51 241 (n=3030) and US$6110 (40 days) (n=246). CONCLUSIONS AND RELEVANCE: Per person costs of injuries and violence are important to monitor the economic burden of injuries and assess the value of prevention strategies.

An electrochemical biosensor based on mild reduction-activated CRISPR/Cas12a system for sensitive detection of circulating tumor cells.

Circulating tumor cell (CTC) has been a valuable biomarker for the diagnosis of breast cancer, while folate receptor is a kind of cell surface receptor glycoprotein which is overexpressed in breast cancer. In this work, we have designed and fabricated an electrochemical biosensor for sensitive detection of folate receptor-positive CTCs based on mild reduction assisted CRISPR/Cas system. Specifically, folate functionalized magnetic beads are firstly prepared to capture CTCs owing to the strong affinity between folate and the folate receptors on the surface of cells. Then, the cell membranes are treated by mild reduction so as to expose a large number of free sulfhydryl groups, which can be coupled with maleimide-DNA to introduce the signal amplified CRISPR/Cas12a system. After the trans-cleavage activity of CRISPR/Cas12a is activated, the long chain DNA modified with electroactive molecules methylene blue can be randomly cleaved into short DNA fragments, which are then captured on the graphite electrode through the host-guest recognition with cucurbit [7]uril, generating highly amplified electrochemical signal corresponding to the number of CTCs. The electrochemical biosensor not only demonstrates the sensitivity with a low detection limit of 2 cells/mL, but also highlights its excellent selectivity and stability in complex environment. Therefore, our biosensor may provide an alternative tool for the analysis of CTCs.

Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.

UBE2D3 facilitates NHEJ by orchestrating ATM signalling through multi-level control of RNF168.

Maintenance of genome integrity requires tight control of DNA damage response (DDR) signalling and repair, with phosphorylation and ubiquitination representing key elements. How these events are coordinated to achieve productive DNA repair remains elusive. Here we identify the ubiquitin-conjugating enzyme UBE2D3 as a regulator of ATM kinase-induced DDR that promotes non-homologous end-joining (NHEJ) at telomeres. UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both mediated by RNF168 upon ATM activation. Additionally, UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated phosphorylation of KAP1-S824. Mechanistically, defective KAP1-S824 phosphorylation and telomeric NHEJ upon UBE2D3-deficiency are linked to RNF168 hyperaccumulation and aberrant PP2A phosphatase activity. Together, our results identify UBE2D3 as a multi-level regulator of NHEJ that orchestrates ATM and RNF168 activities. Moreover, they reveal a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of KAP1 phosphorylation.

Secure optical communication system based on polarization regulation of the data fragmentation multipath transmission technology.

We propose and demonstrate a data fragment multipath transmission scheme to achieve a secure optical communication based on polarization regulation. A dual-polarization Mach-Zehnder modulator (DPMZM) is driven by digital signals which are scattered by field-programmable gate array (FPGA) and transmitted in multiple paths. By utilizing two orthogonal polarization states, we have achieved a signal transmission under different optical parameters, and the transmission rate of the two paths can reach over 10 Gbps through a 20 km fiber with 2.5 Gbps hopping rate. In addition, we establish a theoretical model to analyze the security of the system and simulate brute force cracking; the probability of cracking the minimum information unit is 1.53 × 10-53. This proves that it is difficult to obtain a user data even using the fastest computers. Our scheme has provided, to our knowledge, a new approach for physical layer security.

Four new polyketides from an endophytic fungus Talaromyces muroii.

In our continuous work on the isolation of endophytes, the endophytic fungal strain YIMF00209 was obtained from the roots of Gmelina arborea, which is an ethnic medicinal plant mainly distributed in Southeast Asia. The fermentation extracts of the strain exhibited significant antimicrobial activities against Staphylococcus aureus, Fusarium solani, and Escherichia coli. Based on morphological characteristics and phylogenetic analysis, it was identified as Talaromyces muroii. Four new polyketides, talaromurolides A-D (1-4), along with 26 known compounds (5-30), were isolated from the culture broth of the strain in two different media. Their structures were identified based on HRESIMS, NMR, and CD spectral data. Among them, compounds 2, 4-6, 19, 22, 24, 27, 28, and 30 were isolated from the fermentation broth in CYM medium; compounds 1, 3, 7-18, 20, 21, 23, 25, 26, and 29 were obtained from the fermentation broth in PDB medium; and compounds 2, 5, and 30 were existed in both two media. Compounds 6-9, 12, 16, 20, 21, 23, 25, and 29 were obtained from the genus Talaromyces for the first time. The antimicrobial activities of several compounds were assayed against six pathogens. Compound 1 exhibited inhibitory activities against S. aureus, E. coli, Candida albicans, Salmonella typhimurium, and Botrytis cinerea with MIC value of 64 µg/mL. Compound 25 exhibited antibacterial activity against E. coli with MIC value of 32 µg/mL.

The incidence of immune-related adverse events (irAEs) and their association with clinical outcomes in advanced renal cell carcinoma and urothelial carcinoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: This study aimed to summarize the occurrence of immune-related adverse events (irAEs) and further evaluate their association with clinical outcomes in patients with advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs). METHODS: A comprehensive search of PubMed, Embase, and the Cochrane Library up to December 2023 was conducted to identify eligible studies. The details of irAEs and data regarding their correlation with clinical outcomes were extracted. R software was used for meta-analysis. RESULTS: A total of 27 studies involving 6148 patients with RCC or UC were included. The pooled overall incidence for any-grade and grade ≥ 3 irAEs was 44.2 % (95 % CI: 38.1 %-50.5 %) and 15.7 % (95 % CI: 11.4 %-21.1 %), respectively. Compared to those without any irAEs, patients with irAEs showed improved PFS (HR = 0.44, 95 % CI: 0.35-0.56, p < 0.01) and OS (HR = 0.47, 95 % CI: 0.42-0.51, p < 0.01), as well as higher ORR (OR = 3.59, 95 % CI: 3.01-4.29, p < 0.01) and DCR (OR = 4.23, 95 % CI: 3.06-5.84, p < 0.01). Subgroup analysis indicated that clinical outcome improvements were associated with the occurrence of irAEs, regardless of tumor type or ICI agent. Notably, patients with cutaneous irAEs, thyroid dysfunction, and grade ≤ 2 irAEs had a higher probability to achieve better survival benefits from ICI-based therapy, while pulmonary irAEs and grade ≥ 3 irAEs seemed to have a negative impact on OS. Additionally, systemic glucocorticoids administration did not affect survival outcomes. CONCLUSION: Our findings suggest that the occurrence of irAEs could be considered as a potential prognostic factor for predicting the efficacy of ICIs in patients with advanced RCC and UC.

Regional and rural-urban patterns in the prevalence of diagnosed hypertension among older U.S. adults with diabetes, 2005-2017.

BACKGROUND: Hypertension prevalence among the overall US adult population has been relatively stable during the last two decades. However, whether this stabilization has occurred across rural-urban communities and across different geographic regions is unknown, particularly among older adults with diabetes who are likely to have concomitant cardiovascular risk factors. METHODS: This serial cross-sectional analysis used the 5% national sample of Medicare administrative claims data (n = 3,516,541) to examine temporal trends (2005-2017) in diagnosed hypertension among older adults with diabetes, across urban-rural communities and US census regions (Northeast, Midwest, South, and West). Joinpoint regression was used to obtain annual percent change (APC) in hypertension prevalence across rural-urban communities and geographic regions, and multivariable adjusted regression was used to assess associations between rural-urban communities and hypertension prevalence. RESULTS: The APC in the prevalence of hypertension was higher during 2005-2010, and there was a slowdown in the increase during 2011-2017 across all regions, with significant variations across rural-urban communities within each of the regions. In the regression analysis, in the adjusted model, older adults living in non-core (most rural) areas in the Midwest (PR = 0.988, 95% CI: 0.981-0.995) and West (PR = 0.935, 95% CI: 0.923-0.946) had lower hypertension prevalence than their regional counterparts living in large central metro areas. CONCLUSIONS: Although the magnitudes of these associations are small, differences in hypertension prevalence across rural-urban areas and geographic regions may have implications for targeted interventions to improve chronic disease prevention and management.

Development of quantitative high-throughput screening assays to identify, validate, and optimize small-molecule stabilizers of misfolded ß-glucocerebrosidase with therapeutic potential for Gaucher disease and Parkinson's disease.

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small pro-luminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT-GBA1 transgene into an intragenic safe-harbor locus in GBA1-knockout H4 (neuroglioma) cells. This GD cell model was amenable to lead discovery via titration-based quantitative high-throughput screening and lead optimization via structure-activity relationships. A primary screen of 10,779 compounds from the NCATS bioactive collections identified 140 stabilizers of HiBiT-GCase-L444P, including both pharmacological chaperones (ambroxol and non-inhibitory chaperone NCGC326) and proteostasis regulators (panobinostat, trans-ISRIB, and pladienolide B). Two complementary high-content imaging-based assays were deployed to triage hits: the fluorescence-quenched substrate LysoFix-GBA captured functional lysosomal GCase activity, while an immunofluorescence assay featuring antibody hGCase-1/23 provided direct visualization of GCase lysosomal translocation. NCGC326 was active in both secondary assays and completely reversed pathological glucosylsphingosine accumulation. Finally, we tested the concept of combination therapy, by demonstrating synergistic actions of NCGC326 with proteostasis regulators in enhancing GCase-L444P levels. Looking forward, these physiologically-relevant assays can facilitate the identification, pharmacological validation, and medicinal chemistry optimization of new chemical matter targeting GCase, ultimately leading to a viable therapeutic for two protein-misfolding diseases.

Small molecule drug discovery for glioblastoma treatment based on bioinformatics and cheminformatics approaches.

Background: Glioblastoma (GBM) is a common and highly aggressive brain tumor with a poor prognosis for patients. It is urgently needed to identify potential small molecule drugs that specifically target key genes associated with GBM development and prognosis. Methods: Differentially expressed genes (DEGs) between GBM and normal tissues were obtained by data mining the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Gene function annotation was performed to investigate the potential functions of the DEGs. A protein-protein interaction (PPI) network was constructed to explore hub genes associated with GBM. Bioinformatics analysis was used to screen the potential therapeutic and prognostic genes. Finally, potential small molecule drugs were predicted using the DGIdb database and verified using chemical informatics methods including absorption, distribution, metabolism, excretion, toxicity (ADMET), and molecular docking studies. Results: A total of 429 DEGs were identified, of which 19 hub genes were obtained through PPI analysis. The hub genes were confirmed as potential therapeutic targets by functional enrichment and mRNA expression. Survival analysis and protein expression confirmed centromere protein A (CENPA) as a prognostic target in GBM. Four small molecule drugs were predicted for the treatment of GBM. Conclusion: Our study suggests some promising potential therapeutic targets and small molecule drugs for the treatment of GBM, providing new ideas for further research and targeted drug development.

Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki67.

BACKGROUND: KI67 is a well-known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa). METHODS: Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan-Meier curve and Cox regression analysis. The endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%-30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67-positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA-PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA-PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035). CONCLUSIONS: This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.

Agreements between the Global Leadership Initiative on Malnutrition using left calf circumference as criterion for reduced muscle mass and the Patient-Generated Subjective Global Assessment, and the Global Leadership Initiative on Malnutrition using the a.

Introduction: Objective: this study aimed to explore the agreements between the Global Leadership Initiative on Malnutrition (GLIM) using left calf circumference (CC) as criterion for reduced muscle mass and the Patient-Generated Subjective Global Assessment (PG-SGA), or GLIM using appendicular skeletal muscle index (ASMI) for the diagnosis of malnutrition in gastric cancer patients. Methods: the Nutritional Risk Screening 2002 (NRS 2002) was used as nutritional risk screening. PG-SGA and GLIM were applied for malnutrition diagnosis. Agreements were evaluated by Kappa, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the curve (AUC). Results: a total of 405 gastric cancer patients were included. The values of Kappa, sensitivity, specificity, PPV, NPV, accuracy and AUC were 0.463, 67.9 %, 87.3 %, 92.9 %, 52.8 %, 73.6 % and 0.776, and 0.496, 76.7 %, 78.0 %, 89.4 %, 57.9 %, 77.0 % and 0.773, respectively, between GLIM using CC with or without NRS 2002 and PG-SGA. All values of agreement were higher than 0.800 or 80.0 % between GLIM using left CC and GLIM using ASMI. Conclusion: the agreements were both acceptable between GLIM using left CC and PG-SGA, and GLIM using ASMI. Left calf circumference can be one of the credible references indicating a reduced muscle mass in patients with gastric cancer.

Introducción: Objetivo: este estudio tenía como objetivo explorar los acuerdos entre la Iniciativa Global de Liderazgo en Malnutrición (GLIM) utilizando la circunferencia de la pantorrilla izquierda (CC) como criterio de masa muscular reducida y la Evaluación Global Subjetiva Generada por el Paciente (PG-SGA), o la GLIM utilizando el índice de músculo esquelético apendicular (ASMI) para el diagnóstico de malnutrición en pacientes con cáncer gástrico. Métodos: se utilizó el Cribado de Riesgo Nutricional 2002 (NRS 2002) como cribado de riesgo nutricional. PG-SGA y GLIM se utilizaron para el diagnóstico de desnutrición. Los acuerdos se evaluaron mediante Kappa, sensibilidad, especificidad, valor predictivo positivo (VPP), valor predictivo negativo (VPN), exactitud y área bajo la curva (AUC). Resultados: se incluyó un total de 405 pacientes con cáncer gástrico. Los valores de Kappa, sensibilidad, especificidad, VPP, VPN, exactitud y AUC fueron de 0,463, 67,9 %, 87,3 %, 92,9 %, 52,8 %, 73,6 % y 0,776, y de 0,496, 76,7 %, 78,0 %, 89,4 %, 57,9 %, 77,0 % y 0,773, respectivamente, entre la GLIM utilizando CC con o sin NRS 2002 y PG-SGA. Todos los valores de concordancia fueron superiores a 0,800 u 80,0 % entre la GLIM utilizando la CC izquierda y la GLIM utilizando el ASMI. Conclusión: los acuerdos fueron aceptables entre la GLIM utilizando la CC izquierda y la PG-SGA, y la GLIM utilizando el ASMI. La circunferencia de la pantorrilla izquierda puede ser una de las referencias creíbles que indiquen reducción de la masa muscular en los pacientes con cáncer gástrico.

The impact of general anesthesia on the outcomes of preterm infants with gestational age less than 32 weeks delivered via cesarean section.

Background: Recent advancements in China's perinatal and neonatal intensive care have significantly reduced neonatal mortality, yet preterm births before 32 weeks remain the primary cause of neonatal fatalities and contribute to long-term disabilities. The prognosis of very preterm infants (VPIs) is significantly affected by factors including the intrauterine environment, delivery method and neonatal intensive care. Cesarean section which often used for preterm births has implications that are not fully understood, particularly concerning the type of anesthesia used. This study examines the impact of general anesthesia (GA) during cesarean delivery on VPI outcomes, aiming to identify strategies for mitigating GA-associated risks. Methods: This cohort study analyzed 1,029 VPIs born via cesarean section under 32 weeks' gestation at our single-center from 1 January 2018, to 31 December 2022. Detailed medical records, encompassing perioperative information, maternal data and neonatal outcomes were meticulously examined. The primary aim of this investigation was to compare maternal characteristics and neonatal outcomes between VPIs delivered under GA and neuraxial anesthesia (NA). A significance level of p < 0.05 was established. Results: Of the 1,029 VPIs analyzed, 87.95% (n = 905) were delivered via NA and 12.05% (n = 124) via GA. Mothers with hypertensive pregnancy diseases and emergency operations were more inclined to choose GA. VPIs delivered under GA showed a lower Apgar score at one and 5 minutes (p < 0.01), increased need for tracheal intubation resuscitation (32.2% vs. 12.2%, p < 0.01) and a greater incidence of severe neurological injury (SNI) (14.5% vs. 5%, p < 0.01). Multivariable analysis revealed GA was significantly associated with lower Apgar scores at one (OR 6.321, 95% CI 3.729-10.714; p < 0.01) and 5 minutes (OR 4.535, 95% CI 2.975-6.913; p < 0.01), higher risk of tracheal intubation resuscitation (OR = 3.133, 95% CI = 1.939-5.061; p < 0.01) and SNI (OR = 3.019, 95% CI = 1.615-5.643; p < 0.01). Furthermore, for VPIs delivered under GA, a prolonged interval from skin incision to fetus delivery was associated with a lower 5-min Apgar score (p < 0.01). Conclusion: This study revealed the significant impact of GA on adverse outcomes among VPIs. In cases when GA is required, proactive measures should be instituted for the care of VPIs such as expediting the interval from skin incision to fetal delivery.

Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.

Comparison of the efficacy for early warning systems in predicting obstetric critical illness.

OBJECTIVE: To validate the accuracy of four early warning scores for early identification of women at risk. METHODS: This was a retrospective study of pregnant women admitted in obstetrics Critical Care Unit (ICU). Capacity of the Modified Obstetric Early Warning Score (MOEWS), ICNARC Obstetric Early Warning Score (OEWS), Maternal Early Obstetric Warning System (MEOWS chart), and Maternal Early Warning Trigger (MEWT) were compared in predicting severe maternal morbidity. Area under receiver operator characteristic (AUROC) curve was used to evaluate the predictive performance of scoring system. RESULTS: A total of 352 pregnant women were enrolled and 290 were identified with severe maternal morbidity. MOEWS was more sensitive than MEOWS chart, ICNARC OEWS and MEWT (96.9 % vs. 83.4 %, 66.6 % and 44.8 %). MEWT had the highest specificity (98.4 %), followed by MOEWS (83.9 %), ICNARC OEWS (75.8 %) and MEOWS chart (48.4 %). AUROC of MOEWS, ICNARC OEWS, MEOWS chart, and MEWT for prediction of maternal mortality were 0.91 (95 % CI: 0.874-0.945), 0.765(95 % CI: 0.71-0.82), 0.657(95 % CI: 0.577-0.738), and 0.716 (95 % CI, 0.659-0.773) respectively. MOEWS had the highest AUCs in the discrimination of serious complications in hypertensive disorders, cardiovascular disease, obstetric hemorrhage and infection. For individual vital signs, maximum diastolic blood pressure (DBP), maximum systolic blood pressure (SBP), maximum respiratory rate (RR) and peripheral oxygen saturation (SPO2) demonstrated greater predictive ability. CONCLUSION: MOEWS is more accurate than ICNARC OEWS, MEOWS chart, and MEWT in predicting the deterioration of women. The prediction ability of DBP, SBP, RR and SPO2 are more reliable.

Molecular complexity of intraductal carcinoma of the prostate.

Intraductal carcinoma of the prostate (IDC-P) is an aggressive subtype of prostate cancer characterized by the growth of tumor cells within the prostate ducts. It is often found alongside invasive carcinoma and is associated with poor prognosis. Understanding the molecular mechanisms driving IDC-P is crucial for improved diagnosis, prognosis, and treatment strategies. This review summarizes the molecular characteristics of IDC-P and their prognostic indications, comparing them to conventional prostate acinar adenocarcinoma, to gain insights into its unique behavior and identify potential therapeutic targets.