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Background: Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood., Methods: Here, through computational genomics and proteomics approaches, we analyzed the functional and clinical relevance of CMP expression in GBM at bulk, single cell, and spatial anatomical resolution., Results: We identified genes encoding CMPs whose expression levels categorize GBM tumors into CMP expression-high (M-H) and CMP expression-low (M-L) groups. CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells, and immune checkpoint gene expression. Anatomical and single-cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene CMP expression signature, termed Matrisome 17 (M17) signature that further refines the prognostic value of CMP genes. The M17 signature is a significantly stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, potentially predicts responses to PD1 blockade., Conclusion: The matrisome gene expression signature provides a robust stratification of GBM patients by survival and potential biomarkers of functionally relevant GBM niches that can mediate mesenchymal-immune cross talk. Patient stratification based on matrisome profiles can contribute to selection and optimization of treatment strategies., Competing Interests: Declaration of interests Kyuson Yun is a co-founder of EMPIRI, Inc. Zeynep Dereli is a co-founder of Vivoz Biolabs.

Background: This study aimed to determine the link between water consumption and abdominal obesity in individuals aged 19 years and above, utilizing a sample from the 8th Korea National Health and Nutrition Examination Survey., Methods: Participants were divided into two groups based on their water intake: those meeting adequate intake (≥5 cups for men and ≥4 cups for women) and those with inadequate intake (<5 cups for men and <4 cups for women). Multivariate logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders., Results: Compared with the inadequate water intake group, the adequate water intake group showed a lower adjusted OR for abdominal obesity (adjusted OR, 0.874; 95% CI, 0.770-0.992). In the subgroup analysis, the adjusted OR for abdominal obesity in the 19-39 age group was 0.712 (95% CI, 0.520-0.974). However, no significant association was observed in the 40-64 and 65 or higher age groups., Conclusion: Our findings indicate that sufficient water consumption may be negatively associated with abdominal obesity in adults, particularly among young adults; however, this association may not extend to older age groups.

Importance: Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation., Objectives: To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants., Design, Setting, and Participants: This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, American Association for Cancer Research Project GENIE, and cBioPortal for Cancer Genomics. The cohort comprised patients with BTCs who underwent genomic testing., Main Outcome and Measure: The main outcome was mOS, defined as date of diagnosis to date of death, which was measured in months., Results: A total of 7457 patients (n = 3773 males [50.6%]; mean [SD] age, 63 [5] years) with BTCs and genomic testing were included. Of these patients, 5813 had clinical outcome data available, in whom 1000 KRAS-mutated BTCs were identified. KRAS allelic variants were highly prevalent in perihilar cholangiocarcinoma (28.6%) and extrahepatic cholangiocarcinoma (36.1%). Thirty-six KRAS allelic variants were identified, and the prevalence rates in descending order were G12D (41%), G12V (23%), and Q61H (8%). The variant G12D had the highest mOS of 25.1 (95% CI, 22.0-33.0) months compared with 22.8 (95% CI, 19.6-31.4) months for Q61H and 17.8 (95% CI, 16.3-23.1) months for G12V variants. The majority of KRAS-mutated BTCs (98.9%) were not microsatellite instability-high and had low tumor mutational burden (ranging from a median [IQR] of 1.2 (1.2-2.5) to a mean [SD] of 3.3 [1.3]). Immune profiling through RNA sequencing of KRAS and NRAS-mutated samples showed a pattern toward a more immune-inflamed microenvironment with higher M1 macrophage activation (0.16 vs 0.12; P = .047) and interferon-γ expression compared with wild-type tumors. The G12D variant remained the most common KRAS allelic variant in all patient ancestries. Patients with admixed American ancestry had the highest proportion of G12D variant (45.0%)., Conclusions and Relevance: This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6 , which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death.

Background: Residual fragments (RFs) after percutaneous nephrolithotomy (PCNL) have a significant impact on patients' quality of life and clinical course. There is a paucity of studies that evaluate the natural history of RFs after PCNL. The objective of this study is to compare rates of reintervention, complications, stone growth, and passage in patients with RFs >4, ≤4, and ≤2 mm after PCNL. Methods: Sites from the Endourologic Disease Group for Excellence (EDGE) research consortium examined data of PCNL patients from 2015 to 2019 with at least 1-year follow-up. RF passage, regrowth, reintervention, and complications were recorded and RFs were stratified into >4 and ≤4 mm groups, as well as >2 and ≤2 mm groups. Potential predictors for stone-related events after PCNL were determined using multivariable logistic regression analysis. It was hypothesized that larger RF thresholds would result in lower passage rates, faster regrowth, and greater clinically significant events (complications and reinterventions) than smaller RF thresholds. Results: A total of 439 patients with RFs >1 mm on CT postoperative day 1 were included in this study. For RFs >4 mm, rates of reintervention were found to be significantly higher and Kaplan-Meier curve analysis showed significantly higher rates of stone-related events. Passage and RF regrowth were not found to be significantly different compared with RFs ≤4 mm. However, RFs ≤2 mm had significantly higher rates of passage, and significantly lower rates of fragment regrowth (>1 mm), complications, and reintervention compared with RFs >2 mm. On multivariable analysis, older age, body mass index, and RF size were found to be predictive of stone-related events. Conclusions: With the largest cohort to date, this study by the EDGE research consortium further confirms that clinically insignificant residual fragment is problematic for patients after PCNL, particularly in older more obese patients with larger RFs. Our study underscores the importance of complete stone clearance post-PCNL and challenges the use of Clinically insignificant residual fragment (CIFR).

The interactions between tumor intrinsic processes and immune checkpoints can mediate immune evasion by cancer cells and responses to immunotherapy. It is, however, challenging to identify functional interactions due to the prohibitively complex molecular landscape of the tumor-immune interfaces. We address this challenge with a statistical analysis framework, immuno-oncology gene interaction maps (ImogiMap). ImogiMap quantifies and statistically validates tumor-immune checkpoint interactions based on their co-associations with immune-associated phenotypes. The outcome is a catalog of tumor-immune checkpoint interaction maps for diverse immune-associated phenotypes. Applications of ImogiMap recapitulate the interaction of SERPINB9 and immune checkpoints with interferon gamma (IFNγ) expression. Our analyses suggest that CD86-CD70 and CD274-CD70 immunoregulatory interactions are significantly associated with IFNγ expression in uterine corpus endometrial carcinoma and basal-like breast cancer, respectively. The open-source ImogiMap software and user-friendly web application will enable future applications of ImogiMap. Such applications may guide the discovery of previously unknown tumor-immune interactions and immunotherapy targets., (© 2023. The Author(s).)

Introduction: For treatment of nephrolithiasis, ambulatory percutaneous nephrolithotomy (aPCNL) is growing in popularity for select patients. The aim of this study was to investigate the safety and efficacy of a set of aPCNL selection criteria as well as search for predictors of failed aPCNL resulting in inpatient admission. Materials and Methods: We reviewed all percutaneous nephrolithotomy (PCNL) patients from 2016 to 2020. A total of 175 met selection criteria for aPCNL and were included. Primary outcome was safety and efficacy, and secondary outcome was to identify predictors of inpatient stay. Demographic and perioperative data were analyzed with both descriptive and inferential statistics. Results: In total, between 2016 and 2020, 552 patients underwent PCNL, with 175 of them meeting criteria for aPCNL. One hundred thirty-four of the 175 (76.6%) of these patients were discharged the same day as the surgery and 41 patients were admitted. On univariate analysis, patients who required upper pole access or multiple accesses ( p  = 0.038) American Society of Anesthesiologists >2 ( p  = 0.005), or postoperative nephrostomy (PCN) tube ( p  < 0.001) were more likely to be admitted after surgery. On multivariate analysis, only postoperative PCN was significantly associated with admission ( p  = 0.015). Regarding reasons for unsuccessful aPCNL, 19.5% of admissions were attributed to intraoperative complications, 7% to social causes, 12.2% to postoperative complications, 14.6% to uncontrolled pain, and 34.1% to unexpected intraoperative procedures. Conclusions: aPCNL using selection criteria is safe and effective, with postoperative PCN predicting the possible necessity for conversion to inpatient admission. Furthermore, our study provides a practical algorithm for those opting to provide aPCNL to patients.

Introduction: The objective of this process improvement project was to determine the effect of enhanced recovery after surgery (ERAS) protocol for percutaneous nephrolithotomy (PCNL) patients with respect to quality of life (QOL) and pain management in the postoperative recovery period. Methods: An electronic-based medical record ERAS orders protocol for PCNL was instituted at an academic medical center in July 2020. The protocol utilized a pain control regimen designed to minimize opioid medication use postoperatively. We prospectively evaluated PCNL patients' QOL through the Wisconsin Stone Quality of Life (WISQOL) survey and Patient-Reported Outcomes Measurement System (PROMIS) at routine perioperative visits. To assess any opioid reduction benefit of the ERAS protocol, we reviewed an age-matched historical cohort n  = 66 (before ERAS implementation) to serve as a comparison cohort with respect to opioid usage. Results: After an inception cohort of 95 patients, 55 ERAS patients remained available for assessment with the WISQOL and PROMIS surveys. In comparison with the non-ERAS cohort, the ERAS cohort represented larger stones, more supine positioning, higher blood loss, shorter hospital stay, and more use of access sheath. ERAS patients received a significantly lower amount of opioids compared with non-ERAS patients upon discharge narcotic usage (116.13 morphine milliequivalent [MME] vs 39.57 MME, p  = 0.0001). Compared with their preoperative evaluation, the ERAS cohort had significantly improved QOL scores at 1 week, which sustained through 8 weeks postoperatively. Moreover, pain intensity and pain interference scores were improved at 8 weeks postoperatively for ERAS patients compared with their preoperative time point. Conclusions: We demonstrate that standardizing medications in early efforts toward a PCNL ERAS protocol is feasible and allows for reduced opioid use by patients while achieving early and sustained postprocedure QOL.

Myocardial interstitial fibrosis causes left ventricular stiffness and diastolic dysfunction. Despite its clinical significance, treatment options are limited. The flavonoid baicalein, extracted from roots of a Chinese medicinal plant, Scutellaria baicalensis Georgi was shown to inhibit liver fibrosis. This study sought to investigate whether chronic treatment with baicalein could attenuate myocardial fibrosis in spontaneously hypertensive rats (SHR). SHR were treated daily with baicalein while the control group received vehicle. At the end of study, SHR control group developed significant myocardial fibrosis that was attenuated by baicalein treatment for 4 and 12 weeks. Rats treated with baicalein were protected against an increase in heart to body weight ratio, plasma level of brain natriuretic peptides, intraventricular septum thickness, myocardial collagen volume of left ventricle (all P<0.05, respectively). The antifibrotic effects of baicalein were further illustrated by the suppressed expression of left ventricle pro-collagens I and III accompanied by the decreased expression of 12-lipoxygenase, and by reduced expression and activity of matrix metallopeptidase 9 and extracellular signal-regulated kinases. The present results show for the first time that baicalein can inhibit cardiac fibrosis in hypertensive rats., (Copyright © 2011 Elsevier B.V. All rights reserved.)

EGF receptor transactivation has been known for more than ten years. It is a signal pathway in which a G-protein-coupled receptor (GPCR) signal leads to release of a growth factor, which in turn activates the EGF receptor-tyrosine kinase in the same or adjacent cells. Astrocytes express a number of GPCRs and play key roles in brain function. Astrocytic transactivation is of special interest, since its autocrine effect may regulate gene expression and alter cell functions in the cells themselves and its paracrine effect may provide additional opportunities for cross-talk between astrocytes and their neighbors, such as neurons. The signal pathways of EGF transactivation are complicated. This does not only apply to the pathways leading to shedding of growth factor(s), but also to the downstream signal pathways of the EGF receptor, i.e., MAPK and PI3K. The latter may vary according to the type of growth factor released, the sites of tyrosine phosphorylation on the EGF receptor, and the duration of the phosphorylation. Using primary cell cultures we have found that dexmedetomidine, a specific alpha(2)-adrenergic receptor, induced shedding of HB-EGF from astrocytes, which in turn transactivated EGF receptors and stimulated astrocytic c-Fos and FosB expression. At the same time released HB-EGF protected neurons from injury caused by H(2)O(2). We have also confirmed dexmedetomidine transactivation in the brain in vivo. EGF transactivation by 5-HT(2B) receptor stimulation was responsible for up-regulation of cPLA(2) in astrocytes by fluoxetine, an antidepressant and inhibitor of the serotonin transporter, which also is a specific 5-HT(2B) agonist., (Copyright 2010 Elsevier Ltd. All rights reserved.)

In order to demonstrate the potential therapeutic effect of two flavonoids, Baicalein and Wogonin, on suppression of pathological myocardial fibrosis in hypertension, we investigated their in vitro effects on collagen expression in primary cultured cardiac fibroblasts isolated from neonatal normotensive (WKY) and hypertensive (SHR) rats. Our results showed that over-expression of collagen mRNA and protein induced in cardiac fibroblasts by angiotensin (AngII) could be attenuated significantly by both flavonoids at an optimal dosage (30 microM; P < 0.01). Results of immunoblots showed that expression of 12-LO level, p-ERK/ ERK ratio and MMP-9 in AngII|-stimulated SHR cardiac fibroblasts were significantly down-regulated by both flavonoids. Our results show that both Baicalein and Wogonin can suppress collagen deposition in AngII-stimulated SHR and WKY cardiac fibroblasts.

Objective: Cyclin-dependent kinase inhibitor 1A (p21) is a negative regulator in the cell cycle. Development of sex-linked lupus-like syndrome in p21-/- mice and reduced p21 gene expression in patients with systemic lupus erythematosus (SLE) compared with those in healthy controls suggested that p21 is a susceptibility gene of SLE. We investigated the same by a case-control association study., Methods: Six single nucleotide polymorphisms, p21US G/A, p21DS C/A, p21-1022 G/A, p21C31 C/A, p21In2 G/C and p21UTR T/C, were genotyped in 516 SLE patients and 693 healthy controls. Association of genotypes and alleles with disease, disease phenotypes, haplotypes construction, linkage disequilibrium analysis and p21 mRNA expression were performed., Results: We found a significant association of p21US A allele (OR = 0.23, 95% CI: 0.14-0.38, P < 0.001) and p21-1022 A allele (OR = 1.95, 95% CI: 1.37-2.78, P < 0.001) with SLE. We identified significant differences in the frequencies of haplotypes ht1-ACACCC, which contains p21US A allele, and ht2-GCACCC, which contains p21-1022 A allele, between SLE patients and controls (P < 0.0001). Besides, the p21US GA was associated with SLE patients suffering from arthritis (P = 0.003). We also observed differential p21 mRNA expressions among different genotypes of p21US and p21-1022 which were statistically significant., Conclusion: Our results suggested that the p21US A allele and p21-1022 A allele were both associated with the development of SLE, and the p21US A allele was associated with arthritis in SLE patients.

Aims: Long-term follow-up studies of colorectal endocrine cell tumours (CRECTs) are rare. Our aim was to correlate pathological features with metastatic potential and long-term survival of CRECTs., Methods: Pathological features of 35 CRECTs were reviewed. Features assessed were the tumour size, local and angio-invasion, growth pattern, cyto-nuclear morphology, mitotic count, mucin production and proliferative activity. CRECTs were also re-classified according to the World Health Organization (WHO) 2000 criteria. The follow-ups ranging from 60 to 132 months was obtained from Singapore National Cancer Registry data., Results: There were five metastatic and 30 non-metastatic tumours. Three of five metastatic tumours resulted in death within 1 year of diagnosis. Features exclusively seen in these three tumours were large size (25mm or more), mitoses > 6/10 high power fields with abnormal forms necrosis and large cell morphology. The features which correlated significantly with metastases were size, local and angioinvasion, primitive growth pattern, coarse chromatin and mitotic count (p < 0.0005), large cells and prominent nucleoli (p = 0.017), MIB1 proliferative index (p = 0.001) and abnormal mitoses and necrosis (p = 0.02). Thirty tumours were reclassified as well-differentiated endocrine cell tumours (WETs), three as well-differentiated endocrine cell carcinomas (WECs) and two were large cell neuroendocrine cell carcinomas (LECs) according to WHO criteria. One of the WECs and both LECs resulted in death., Conclusions: All patients whose tumour was 25 mm or more, showing mitoses of more than 6 per 10 high power fields, with abnormal forms, necrosis and large cell morphology, died of the disease. Size, invasion, presence of discernible mitoses, coarse chromatin, 'primitive' growth pattern and MIB1 index of 4% or more were associated with metastases. LECs are rare but aggressive tumours resulting in early death. All WECs do not behave in the same fashion.

Little is known about the innate immune response to severe acute respiratory syndrome (SARS) coronavirus (CoV) infection. Mannose-binding lectin (MBL), a key molecule in innate immunity, functions as an ante-antibody before the specific antibody response. Here, we describe a case-control study that included 569 patients with SARS and 1188 control subjects and used in vitro assays to investigate the role that MBL plays in SARS-CoV infection. The distribution of MBL gene polymorphisms was significantly different between patients with SARS and control subjects, with a higher frequency of haplotypes associated with low or deficient serum levels of MBL in patients with SARS than in control subjects. Serum levels of MBL were also significantly lower in patients with SARS than in control subjects. There was, however, no association between MBL genotypes, which are associated with low or deficient serum levels of MBL, and mortality related to SARS. MBL could bind SARS-CoV in a dose- and calcium-dependent and mannan-inhibitable fashion in vitro, suggesting that binding is through the carbohydrate recognition domains of MBL. Furthermore, deposition of complement C4 on SARS-CoV was enhanced by MBL. Inhibition of the infectivity of SARS-CoV by MBL in fetal rhesus kidney cells (FRhK-4) was also observed. These results suggest that MBL contributes to the first-line host defense against SARS-CoV and that MBL deficiency is a susceptibility factor for acquisition of SARS.

Objective: The programmed death 1 (PD-1) molecule is a negative regulator of T cells, and a genetic association between PD-1 and systemic lupus erythematosus and rheumatoid arthritis (RA) in Caucasians has been reported. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with RA in the Chinese population., Methods: Three single-nucleotide polymorphisms (SNPs), PD-1.1 G/A, PD-1.3 G/A, and PD-1.5 C/T, were genotyped in 180 patients with RA and 647 healthy controls in a case-control association study. Analyses of the association of genotypes and alleles with disease, haplotype construction, and linkage disequilibrium (LD) were performed., Results: We constructed haplotypes with the alleles of markers PD-1.1 G/A and PD-1.5 C/T and found that the GT haplotype was overrepresented in patients with RA (31%) compared with controls (23%) (P = 0.001, odds ratio [OR] 1.54, 95% confidence interval [95% CI] 1.18-1.99). Among GT double homozygotes the risk of RA was increased even further (OR 2.31, 95% CI 1.31-4.08, P = 0.006). We also observed that the AA genotype of SNP PD-1.1 was associated with a decreased risk for developing RA (OR 0.38, 95% CI 0.15-0.99, P = 0.034). No association for SNP PD-1.5 in RA was found, and SNP PD-1.3 was nonpolymorphic in the Chinese population., Conclusion: Our results support the involvement of PDCD1 as a susceptibility gene for RA in the Chinese population., ((c) 2005, American College of Rheumatology.)

The effects were studied of short-term (1 week) versus long-term (2-3 weeks) fluoxetine treatment of primary cultures of mouse astrocytes, differentiated by treatment with dibutyryl cyclic AMP. From previous experiments it is known that acute treatment with fluoxetine stimulates glycogenolysis and increases free cytosolic Ca2+ concentration ([Ca2+]i]) in these cultures, whereas short-term (one week) treatment with 10 microM down-regulates the effects on glycogen and [Ca2+]i, when fluoxetine administration is renewed (or when serotonin is administered). Moreover, antagonist studies have shown that these responses are evoked by activation of a 5-HT2, receptor that is different from the 5-HT2A receptor and therefore at that time tentatively were interpreted as being exerted on 5-HT2C receptors. In the present study the cultures were found by RT-PCR to express mRNA for 5-HT2A and 5-HT2B receptors, but not for the 5-HT2C receptor, identifying the 5-HT2 receptor activated by fluoxetine as the 5-HT2B receptor, the most recently cloned 5-Ht2 receptor and a 5-HT receptor known to be more abundant in human, than in rodent, brain. Both short-term and long-term treatment with fluoxetine increased the specific binding of [3H]mesulergine, a ligand for alL three 5-HT2 receptors. Long-term treatment with fluoxetine caused an agonist-induced up-regulation of the glycogenolytic response to renewed administration of fluoxetine, whereas short-term treatment abolished the fluoxetine-induced hydrolysis of glycogen. Thus, during a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up-regulated.