CD10 Immunohistochemical Expression in Breast Carcinoma and Its Correlation With Clinicopathological Parameters.

BACKGROUND:  Interaction between the stromal and tumor cells is of crucial importance in breast cancer progression and response to therapy. A literature search has shown that stromal CD10 expression signifies the biological aggressiveness of various epithelial malignancies. Stromal markers are now becoming apparent as novel markers in evaluating the prognosis of invasive breast cancer and have not been studied substantially to date. OBJECTIVES: To study the immunohistochemical expression of CD10 in stromal cells of breast carcinoma and to correlate the expression of CD10 with various clinicopathological prognostic factors such as the size of the tumor, histological grade, lymph node status, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2/neu protooncogene (HER2-neu) status. METHODOLOGY:  In the present study, a hospital-based cross-sectional study was conducted on 50 mastectomy specimens diagnosed with invasive breast carcinoma. The specimens of patients who had received neoadjuvant therapy or chemotherapy were excluded. Size of the tumor, grade of tumor on histopathology, lymph node involvement, and IHC status of ER, PR, and HER2-neu were noted. IHC staining for the CD10 marker was performed, and expression of stromal CD10 was correlated with these clinical-pathological prognostic factors. RESULTS:  CD10 expression in stromal cells of breast carcinoma was seen in 40 (80%) cases, and it showed a statistically significant association with histological grade (χ2 = 17.262; p-value < 0.0001), ER negativity (χ2 = 3.668; p-value < 0.045), and PR negativity (χ2 = 3.926; p-value < 0.048). CONCLUSION: A strong association of stromal CD10 expression with a well-established negative prognostic marker such as a higher tumor grade, ER-negative status, and PR-negative status was noted and thus, stromal CD10 expression can be used as an independent prognostic marker in breast carcinoma.

Codoping Pr3+ and Er3+ into NaLaTi2O6 to realize dual-mode FIR temperature sensing properties.

In this report, a Pr3+/Er3+ doped NaLaTi2O6 phosphor was prepared as self-reference optical thermometer via a typical solid-state sintering method. The phase component, crystal structure and luminescence properties were elaborated in detail. A broad IVCT band along with several narrow 4f-4f excitation bands were readily found when monitored at 608 nm in Pr3+ singly doped NaLaTi2O6 material. In addition, the material showed typical 4f-4f transitions with two dominant bands around 495 nm and 609 nm originating from 3P0 â†’ 3H4 and 1D2 â†’ 3H4, respectively, upon ICVT or Pr3+ unique 4f-4f excitation. In Pr3+, Er3+ co-doped samples, the up-conversion (UC) emission bands around 522 nm, 548 nm and 661 nm, originating from characteristic transitions 2H11/2 â†’ 4I15/2, 4S3/2 â†’ 4I15/2 and 4F9/2 â†’ 4I15/2 of Er3+ ion was found, respectively, upon 980 nm radiation. Besides, the four main bands around 495 nm, 522 nm, 543 nm, 609 nm assigned to Pr3+ 3P0 â†’ 3H4, Er3+ 2H11/2 â†’ 4I15/2, Er3+ 4S3/2 â†’ 4I15/2, Pr3+ 1D2 â†’ 3H4, respectively, can be observed upon 379 nm co-excitation. By monitoring thermal responses emission intensities of versatile transitions under UC and down-shift (DS) excitation modes, good temperature sensitivity and signal discriminability based on FIR technique have been achieved in phosphor NaLaTi2O6:Pr3+, Er3+. Additionally, the maximal absolute temperature sensitivity Sa and relative temperature sensitivity Sr reach 0.0831 K-1 at 294 K and 1.15 % K-1 at 294 K under 980 nm excitation mode, and 0.01742 K-1 at 453 K and 1.826 % K-1 at 294 K under 379 nm excitation mode, respectively, indicating the prepared material in this work can be considered as a latent candidate for optical thermometry. More inspired, this work sets up a new pathway of codoping Pr3+ and Er3+ into suitable matrices to devise excellent FIR optical thermometry.

Magnesium polypeptide combined with microbially induced calcite precipitation for remediation of lead contamination in phosphate mining wasteland soil.

Soil Pb contamination is inevitable, as a result of phosphate mining. It is essential to explore more effective Pb remediation approaches in phosphate mining wasteland soil to ensure their viability for a gradual return of soil quality for cultivation. In this study, a Pb-resistant urease-producing bacterium, Serratia marcescens W1Z1, was screened for remediation using microbially induced carbonate precipitation (MICP). Magnesium polypeptide (MP) was prepared from soybean meal residue, and the combined remediation of Pb contamination with MP and MICP in phosphate mining wasteland soil was studied. Remediation of Pb using a combination of MP with MICP strain W1Z1 (WM treatment) was the most effective, with the least exchangeable Pb at 30.37% and the most carbonate-bound Pb at 40.82%, compared to the other treatments, with a pH increase of 8.38. According to the community analysis, MP moderated the damage to microbial abundance and diversity caused by MICP. Total nitrogen (TN) was positively correlated with Firmicutes, pH, and carbonate-bound Pb. Serratia inoculated with strain W1Z1 were positively correlated with bacteria belonging to the Firmicutes phylum and negatively correlated with bacteria belonging to Proteobacteria. The available phosphate (AP) in the phosphate mining wasteland soil could encapsulate the precipitated Pb by ion exchange with carbonate, making it more stable. Combined MP-MICP remediation of Pb contamination in phosphate mining wasteland soil was effective and improved the soil microenvironment.

Influences of Weizmannia coagulans PR06 Fermentation on Texture, Cooking Quality and Starch Digestibility of Oolong Tea-Fortified Rice Noodles.

Weizmannia coagulans is increasingly employed in food processing owing to its health benefits. Our previous research developed Oolong tea-fortified rice noodles with unique flavor and potent antioxidant activity; however, their texture still requires improvement. In this study, Oolong tea-fortified rice noodles were fermented using W. coagulans PR06 at inoculation amounts of 1%, 3%, and 5% (v/v), and assessed for cooking quality, texture, and starch digestibility. The results indicated that fermentation with 3% and 5% W. coagulans PR06 altered the amylopectin length distribution in the rice noodles and increased the degree of starch short-range order. Furthermore, the fermentation process increased the storage modulus (G') and loss modulus (G″) values, decreased the tan δ value, and strengthened the interactions among tea polyphenols, proteins, and starch in the rice flour gel. Consequently, this process increased the hardness and chewiness of the rice noodles, decreased their broken strip rate and cooking loss, and significantly reduced their in vitro starch digestibility. Overall, fermentation with W. coagulans PR06 markedly improved the texture and cooking quality of Oolong tea-fortified rice noodles while effectively delaying starch digestion. This study highlights the potential application of W. coagulans PR06 in developing diverse and functional rice noodle products.

An Autopsy Case of Renal-Limited Granulomatosis With Polyangiitis Presenting With Acute Renal Failure and Initial Delirium.

Granulomatosis with polyangiitis (GPA) has three clinicopathological features, namely, necrotizing granulomatosis of the upper respiratory tract and lungs, focal segmental necrotizing glomerulonephritis of the kidney, and necrotizing vasculitis of small vessels throughout the body. A 92-year-old man with clinically diagnosed probable Alzheimer's disease (AD) exhibited subacute deterioration in cognitive function. On admission, he was diagnosed with acute renal failure with an elevated creatinine level (5.48 mg/dL) as well as severe disturbance of consciousness. Antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3-ANCA) were highly positive with ≥ 350 U/mL. The patient was diagnosed with GPA and was managed with steroid pulse therapy. However, he died without any improvement in renal function. As a result of the autopsy, the patient was diagnosed with definite AD, and his impaired consciousness was found not to be caused by central nervous system involvement due to GPA. As necrotizing crescentic glomerulonephritis was observed, the cause of the acute progressive renal failure was found to be PR3-ANCA-positive GPA. The autopsy revealed no GPA-related lesions in other parts of the body aside from the kidneys. It is rare to encounter cases of PR3-ANCA-positive GPA with renal-limited vasculitis and acute renal failure as the initial manifestation, as in the present case. Making an accurate clinical diagnosis of older patients suffering from various diseases in multiple organs is challenging. Although autopsy has the limitation of a terminal image, it is extremely useful in elucidating the pathophysiology of the older patient in this case.

Orchestra of ligand-activated transcription factors in the molecular symphony of SERPINE 1 / PAI-1 gene regulation.

Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.

Exogenous S1P via S1P receptor 2 induces CTGF expression through Src-RhoA-ROCK-YAP pathway in hepatic stellate cells.

BACKGROUND: Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. METHODS: In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation. RESULTS: Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor. CONCLUSIONS: Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis.

Lysophospholipid receptors in neurodegeneration and neuroprotection.

The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson's disease, Huntington's disease, Rett syndrome, Alzheimer's disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA1, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes.

Efficacy and safety of the S1PR modulator etrasimod in the treatment of moderately to severely active ulcerative colitis during the induction phase: a systematic review and meta-analysis of randomized controlled trials.

Background: The study aims to assess the efficacy and safety of the recently approved S1PR modulator etrasimod in adults with ulcerative colitis during the induction phase through meta-analysis. Methods: A systemic search was performed for randomized controlled trials evaluating the efficacy and safety of the S1PR modulator etrasimod using electronic databases PubMed, Embase, the Cochrane Library, Clinical Trials, and the International Clinical Trials Registry Platform. Three studies with 943 patients met the inclusion criteria and were included in this analysis. The study's primary endpoint was the proportion of patients who achieved clinical remission at week 12. Key secondary endpoints included the proportion of patients with clinical response, endoscopic improvement, and histologic remission. The incidence of adverse effects (AEs), serious AEs (SAEs), and AE-related treatment discontinuation were statistically analyzed to determine the safety of etrasimod. Results: This study revealed that etrasimod is superior to placebo at the primary endpoint clinical remission (OR = 3.09, 95% CI: 2.04-4.69), as well as at the secondary endpoints clinical response (OR = 2.56, 95% CI: 1.91-3.43), endoscopic improvement (OR = 2.15, 95% CI: 1.51-3.05), and histologic remission (OR = 3.39, 95% CI: 2.03-5.68). The proportion of patients with TEAE (OR = 1.34, 95% CI: 1.01-1.78) and SAE (OR = 0.77, 95% CI: 0.41-1.43) was similar between the etrasimod and placebo groups. Patients receiving etrasimod had slightly higher odds of experiencing headache (OR = 2.07, 95% CI: 1.01-4.23), and nausea (OR = 1.84, 95% CI: 0.72-4.72). The incidences of upper respiratory tract infection (OR = 0.79, 95% CI: 0.27-2.32), nasopharyngitis (OR = 0.40, 95% CI: 0.15-1.07), and urinary tract infection (OR = 1.82, 95% CI: 0.59-5.60) were generally lower in the etrasimod groups and no treatment-related serious infections were reported. Conclusion: This study demonstrates that etrasimod is effective in treating moderately to severely active ulcerative colitis with a favorable benefit-risk profile at week 12. Etrasimod shows promise as a potential first-line oral therapy for individuals suffering from this disease. Additional RCTs with larger sample sizes and longer observation periods are needed to confirm the sustained efficacy of etrasimod beyond the initial phase.

Numerical investigation of acoustic cavitation characteristics of a single gas-vapor bubble in soft tissue under dual-frequency ultrasound.

The viscoelastic tissue under dual-frequency ultrasound excitation affects the acoustic cavitation of a single gas-vapor bubble. To investigate the effect of the cavitation dynamics, the Gilmore-Akulichev-Zener (GAZ) model is coupled with the Peng-Robinson equation of state (PR EOS). Results indicate that the GAZ-PR EOS model can accurately estimate the bubble dynamics by comparing with the Gilmore PR EOS and GAZ-Van der Waals (VDW) EOS model. Furthermore, the acoustic cavitation effect in different viscoelastic tissues is investigated, including the radial stress at the bubble wall, the temperature, pressure, and the number of water molecules inside the bubble. Results show that the creep recovery and the relaxation of the stress caused by viscoelasticity can affect the acoustic cavitation of the bubble, which could inhibit the bubble's expansion and reduce the internal temperature and pressure within the bubble. Moreover, the effect of dual-frequency ultrasound on the cavitation of single gas-vapor bubbles is studied. Results suggest that dual-frequency ultrasound could increase the internal temperature of bubbles, the internal pressure of bubbles, and the radial stress at the bubble wall. More importantly, there is a specific optimal combination of frequencies for particular viscoelasticity by exploring the impact of different dual-frequency ultrasound combinations and tissue viscoelasticity on the acoustic cavitation of a single gas-vapor bubble. In conclusion, this study helps to provide theoretical guidance for dual-frequency ultrasound to improve acoustic chemical and mechanical effects, and further optimize its application in acoustic sonochemistry and ultrasound therapy.

Two Decades Rituximab Therapy in Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis.

Remission failure and relapse numerate as one of the main problems in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAVs). The need for new agents that provide effective and safe induction accompanied by sustained remission seems to be urgent in clinical care. The efficacy and safety of rituximab (RTX) for AAVs therapy has been reported in various studies. RTX therapy offers several advantages to treating AAVs patients compared to other therapeutic approaches including reduction of Glucocorticoids (GCs) and conventional Immunosuppressive therapy (IST) usage during both the induction of remission and maintenance phases. This reduction can lead to a lower rate of serious complications making RTX therapy a safer option. It seems that RTX may provide improved clinical outcomes in these patients mediated via B-lymphocyte depletion, Proteinase 3-antineutrophilic cytoplasmic antibody (PR3-ANCA), and myeloperoxidase-antineutrophilic cytoplasmic antibody (MPO-ANCA) titers reduction. In this regard, some uncertainties have been reported to validate the association between such depletion and clinical improvement, as suggested by other sources of autoreactive B cells that did not target with RTX. Due to the prolonged B cell depletion, fixed intervals and adjusted dosage of RTX may be required in patients with AAVs. In this narrative review, we aimed to insight better understand regarding the efficacy of RTX for effective induction and sustained remission in patients with AAVs. It seems that discovering new biomarkers predicting relapse in AAVs patients can lead to future targeted therapy.

Obesity-Associated Breast Cancer: Analysis of Risk Factors and Current Clinical Evaluation.

Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Additionally, obese and postmenopausal women are at higher risk of all-cause and breast cancer-specific mortality compared with non-obese women with breast cancer. In this context, increased levels of estrogens, excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, adipocyte-derived adipokines, hypercholesterolemia, and excessive oxidative stress contribute to the development of breast cancer in obese women. Genetic evaluation is an integral part of diagnosis and treatment for patients with breast cancer. Despite trimodality therapy, the four-year cumulative incidence of regional recurrence is significantly higher. Axillary lymph nodes as well as primary lesions have diagnostic, prognostic, and therapeutic significance for the management of breast cancer. In clinical setting, because of the obese population primary lesions and enlarged lymph nodes could be less palpable, the diagnosis may be challenging due to misinterpretation of physical findings. Thereby, a nomogram has been created as the "Breast Imaging Reporting and Data System" (BI-RADS) to increase agreement and decision-making consistency between mammography and ultrasonography (USG) experts. Additionally, the "breast density classification system," "artificial intelligence risk scores," ligand-targeted receptor probes," "digital breast tomosynthesis," "diffusion-weighted imaging," "18F-fluoro-2-deoxy-D-glucose positron emission tomography," and "dynamic contrast-enhanced magnetic resonance imaging (MRI)" are important techniques for the earlier detection of breast cancers and to reduce false-positive results. A high concordance between estrogen receptor (ER) and progesterone receptor (PR) status evaluated in preoperative percutaneous core needle biopsy and surgical specimens is demonstrated. Breast cancer surgery has become increasingly conservative; however, mastectomy may be combined with any axillary procedures, such as sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection whenever is required. As a rule, SLNB-guided axillary dissection in breast cancer patients who have clinically axillary lymph node-positive to node-negative conversion following neoadjuvant chemotherapy is recommended, because lymphedema is the most debilitating complication after any axillary surgery. There is no clear consensus on the optimal treatment of occult breast cancer, which is much discussed today. Similarly, the current trend in metastatic breast cancer is that the main palliative treatment option is systemic therapy.

Characterization of probiotic strains of Bacillus sp. from fermented palm wine (Nypa fructicans sp.) and exploration of cellulolytic potential for use as an addition in animal feed.

The main objective of this study was to assess cellulolytic probiotic strains from traditional fermented beverages such as palm wine in order to supplement the animal feed and strengthen the gut health of the animal for better digestibility and absorption. In the present study, different types of microbes were isolated from traditionally prepared palm wine and analyzed for their probiotic nature. For any microbe to be probiotic in nature, it has to sustain the harsh conditions of the human gastrointestinal tract such as acid tolerance, bile tolerance at the lower range of pH, and other properties like auto aggregation test, cell surface hydrophobicity test with non-polar hydrocarbons for evaluating its capabilities to adhere to the intestinal cells and antimicrobial nature against pathogens. Bacillus mycoides strain PR04 and Bacillus subtilis strain PR21 were found to be resistant to acid and bile in simulated artificial gastrointestinal tract model, found to be than 55% hydrophobic with xylene and n-hexadecane and also showed antimicrobial activity greater towards pathogenic strains like Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Salmonella typhimurium respectively. The cellulolytic activity of the isolates PR04 and PR21 was evaluated in (0.2-2) % CMC (carboxymethyl cellulose) plate. Bacillus mycoides PR04 and Bacillus subtilis PR21 could degrade carboxymethyl cellulose, filter paper, and sugarcane bagasse. The degradation of sugarcane bagasse was confirmed by Scanning electron microscopy and filter paper degradation after 4 days of incubation at 37 °C. Cellulase gene of the identified Bacillus sp. strains was amplified by primers CF5'-ACAGGATCCGATGAAAACGGTCAATTTCTATTTT-3' and CR5'-ACTCTCGAGATTGGGTTCTGTTCCCAAT-3'. This study proposes potential probiotic Bacillus mycoides PR04 (Accession no. OR625070) and Bacillus subtilis PR21 (Accession no. OR625072) in the application as an animal feed additive to assist in its digestibility and encourage the gut health.

AI-guided identification of risk variants for adrenocortical tumours in TP53 p.R337H carrier children: a genetic association study.

Background: Adrenocortical tumours (ACT) in children are part of the Li-Fraumeni cancer spectrum and are frequently associated with a germline TP53 pathogenic variant. TP53 p.R337H is highly prevalent in the south and southeast of Brazil and predisposes to ACT with low penetrance. Thus, we aimed to investigate whether genetic variants exist which are associated with an increased risk of developing ACT in TP53 p.R337H carrier children. Methods: A genetic association study was conducted in trios of children (14 girls, 7 boys) from southern Brazil carriers of TP53 p.R337H with (n = 18) or without (n = 3) ACT and their parents, one of whom also carries this pathogenic variant (discovery cohort). Results were confirmed in a validation cohort of TP53 p.R337H carriers with (n = 90; 68 girls, 22 boys) or without ACT (n = 302; 165 women, 137 men). Findings: We analysed genomic data from whole exome sequencing of blood DNA from the trios. Using deep learning algorithms, according to a model where the affected child inherits from the non-carrier parent variant(s) increasing the risk of developing ACT, we found a significantly enriched representation of non-coding variants in genes involved in the cyclic AMP (cAMP) pathway known to be involved in adrenocortical tumorigenesis. One among those variants (rs2278986 in the SCARB1 gene) was confirmed to be significantly enriched in the validation cohort of TP53 p.R337H carriers with ACT compared to carriers without ACT (OR 1.858; 95% CI 1.146, 3.042, p = 0.01). Interpretation: Profiling of the variant rs2278986 is a candidate for future confirmation and possible use as a tool for ACT risk stratification in TP53 p.R337H carriers. Funding: Centre National de la Recherche Scientifique (CNRS), Behring Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36-42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.

Structure-Elasticity Relationships in Hybrid-Carrageenan Hydrogels Studied by Image Dynamic Light Scattering, Ultra-Small-Angle Light Scattering and Dynamic Rheometry.

Hybrid-carrageenan hydrogels are characterized using novel techniques based on high-resolution speckle imaging, namely image dynamic light scattering (IDLS) and ultra-small-angle light scattering (USALS). These techniques, used to probe the microscopic structure of the system in sol-gel phase separation and at different concentrations in the gel phase, give access to a better understanding of the network's topology on the basis of fractals in the dense phase. Observations of the architecture and the spatial and the size distributions of gel phase and fractal dimension were performed by USALS. The pair-distance distribution function, P(r), extracted from USALS patterns, is a new methodology of calculus for determining the network's internal size with precision. All structural features are systematically compared with a linear and non-linear rheological characterization of the gels and structure-elasticity relationships are identified in the framework of fractal colloid gels in the diffusion limit.

Navigating the complexity of Polycomb repression: Enzymatic cores and regulatory modules.

Polycomb proteins are a fundamental repressive system that plays crucial developmental roles by orchestrating cell-type-specific transcription programs that govern cell identity. Direct alterations of Polycomb activity are indeed implicated in human pathologies, including developmental disorders and cancer. General Polycomb repression is coordinated by three distinct activities that regulate the deposition of two histone post-translational modifications: tri-methylation of histone H3 lysine 27 (H3K27me3) and histone H2A at lysine 119 (H2AK119ub1). These activities exist in large and heterogeneous multiprotein ensembles consisting of common enzymatic cores regulated by heterogeneous non-catalytic modules composed of a large number of accessory proteins with diverse biochemical properties. Here, we have analyzed the current molecular knowledge, focusing on the functional interaction between the core enzymatic activities and their regulation mediated by distinct accessory modules. This provides a comprehensive analysis of the molecular details that control the establishment and maintenance of Polycomb repression, examining their underlying coordination and highlighting missing information and emerging new features of Polycomb-mediated transcriptional control.

Tumor grade and progesterone receptor status in predicting benefit of chemotherapy in high genomic risk breast cancer.

BACKGROUND: Not all eligible breast cancer (BC) patients could afford the expensive test of 21-gene recurrence score (RS) assay. This study aimed to identify clinicopathological factors associated with high-risk RS and examine whether these factors correlate with the benefit of chemotherapy. RESEARCH DESIGN AND METHODS: Patients diagnosed with early-stage BC, node-negative, and estrogen receptor-positive disease were identified from the Surveillance, Epidemiology, and End Results Oncotype DX database. RESULT: We included 74,605 patients. Those with higher grade (p < 0.001) and progesterone receptor-negative (PR Neg) (p < 0.001) had the highest odds of a high-risk RS. Among them, 3.2%, 10.1%, 39.1%, 18.6%, 41.6%, and 80.1% had high-risk RS tumors in PR-positive (PR Pos)/well-differentiated (G1), PR Pos/moderately differentiated (G2), PR Pos/poorly and/or undifferentiated (G3), PR Neg/G1, PR Neg/G2, and PR Neg/G3 groups, respectively. Receipt of chemotherapy was associated with improved breast cancer-specific survival (p = 0.010) and overall survival (p < 0.001) in high-risk RS cohort. However, there were no survival benefits from chemotherapy in patients with PR Neg/G3 disease and other groups after stratification by grade and PR status (all p ≥ 0.05). CONCLUSION: Our study aids in refining patient selection for the RS testing, which is crucial given its economic implications. However, 21-gene RS remains pivotal for treatment decision-making.

Exploring the Impact of Oxygen Vacancies in Co/Pr-CeO2 Catalysts on H2 Production via the Water-Gas Shift Reaction.

In this study, we utilized various Pr-doped CeO2 catalysts (Pr=5, 10, 20, and 30 wt.%) as a support medium for the dispersion of cobalt (Co) nanoparticles, aiming to investigate the impact of oxygen vacancies on the water-gas shift (WGS) reaction. Different characterization techniques were employed to understand the insights into the structure-activity relationship governing the performance of Pr doped ceria supported Co catalysts towards WGS reaction. Our findings reveal that Co/Pr-CeO2 catalysts at optimum Pr loading (10 wt.%) exhibit a superior CO conversion (88 %) facilitated by the presence of more oxygen vacancies induced by Pr doping into the CeO2 lattice, as opposed to the performance of the pure Co/CeO2 catalytic system. It was also found that the highest activity was obtained at increased intrinsic oxygen vacancies and strong synergy between Co and Pr/CeO2 support, fostering more favorable CO activation at the interfacial sites, thus accounting for the observed enhanced activity.

A2 reactive astrocyte-derived exosomes alleviate cerebral ischemia-reperfusion injury by delivering miR-628.

Ischemia and hypoxia activate astrocytes into reactive types A1 and A2, which play roles in damage and protection, respectively. However, the function and mechanism of A1 and A2 astrocyte exosomes are unknown. After astrocyte exosomes were injected into the lateral ventricle, infarct volume, damage to the blood-brain barrier (BBB), apoptosis and the expression of microglia-related proteins were measured. The dual luciferase reporter assay was used to detect the target genes of miR-628, and overexpressing A2-Exos overexpressed and knocked down miR-628 were constructed. qRT-PCR, western blotting and immunofluorescence staining were subsequently performed. A2-Exos obviously reduced the infarct volume, damage to the BBB and apoptosis and promoted M2 microglial polarization. RT-PCR showed that miR-628 was highly expressed in A2-Exos. Dual luciferase reporter assays revealed that NLRP3, S1PR3 and IRF5 are target genes of miR-628. After miR-628 was overexpressed or knocked down, the protective effects of A2-Exos increased or decreased, respectively. A2-Exos reduced pyroptosis and BBB damage and promoted M2 microglial polarization through the inhibition of NLRP3, S1PR3 and IRF5 via the delivery of miR-628. This study explored the mechanism of action of A2-Exos and provided new therapeutic targets and concepts for treating cerebral ischemia.