A Genomics-Driven Artificial Intelligence-Based Model Classifies Breast Invasive Lobular Carcinoma and Discovers CDH1 Inactivating Mechanisms.

Artificial intelligence (AI)-systems can improve cancer diagnosis, yet their development often relies on subjective histological features as ground truth for training. Here, we developed an AI-model applied to histological whole-slide images (WSIs) using CDH1 bi-allelic mutations, pathognomonic for invasive lobular carcinoma (ILC) in breast neoplasms, as ground truth. The model accurately predicted CDH1 bi-allelic mutations (accuracy=0.95) and diagnosed ILC (accuracy=0.96). A total of 74% of samples classified by the AI-model as having CDH1 bi-allelic mutations but lacking these alterations displayed alternative CDH1 inactivating mechanisms, including a deleterious CDH1 fusion gene and non-coding CDH1 genetic alterations. Analysis of internal and external validation cohorts demonstrated 0.95 and 0.89 accuracy for ILC diagnosis, respectively. The latent features of the AI-model correlated with human-explainable histopathologic features. Taken together, this study reports the construction of an AI-algorithm trained using a genetic rather than histologic ground truth that can robustly classify ILCs and uncover CDH1 inactivating mechanisms, providing the basis for orthogonal ground truth utilization for development of diagnostic AI-models applied to WSI.

Zona incerta mediates early life isoflurane-induced fear memory deficits.

The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments.

Cellular and circuit architecture of the lateral septum for reward processing.

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.

Geriatric nutritional risk index and mortality from all-cause, cancer, and non-cancer in US cancer survivors: NHANES 2001-2018.

Background: Malnutrition is strongly correlated with worsened treatment outcomes, reduced standard of living, and heightened mortality rates among individuals with cancer. Our research explores how the Geriatric Nutritional Risk Index (GNRI), a measure of nutritional status, relates to all-cause mortality, cancer-specific, and non-cancer mortality among middle-aged and older adult cancer patients. Methods: We enrolled 3,253 participants aged 40 and above who were diagnosed with cancer. The data was obtained from the National Health and Nutrition Examination Survey (NHANES) dataset covering the period from 2001 to 2018, with a median follow-up duration of 83 months. According to the GNRI levels, patients in the study were classified into two distinct groups: the group with a low GNRI (<98) and the group with a high GNRI (≥ 98). We conducted a Kaplan-Meier survival analysis to assess how survival rates vary with different nutritional conditions. Multivariable Cox regression analyses were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality, as well as cancer-specific and non-cancer-related mortality. Restricted cubic spline (RCS) analyses and subgroup evaluations were performed to augment the robustness and validity of our findings. Results: A total of 1,171 deaths were documented, with 383 attributed to cancer, and 788 from other causes. After adjusting for potential confounders, the analysis demonstrated that, within a specified range, an elevation in the GNRI is inversely associated with mortality from all causes, cancer-specific, and non-cancer causes. Moreover, Kaplan-Meier survival curves for all-cause, cancer-specific, and non-cancer mortality distinctly showed a more pronounced decrease in survival rates among individuals in the low GNRI group (<98). Notably, the restricted cubic spline regression model (RCS) revealed statistically significant non-linear associations between GNRI scores and mortality rates. The P-values were ≤0.001 for both all-cause and non-cancer mortality, and 0.024 for cancer-specific mortality. Conclusion: Our study conclusively demonstrated a robust correlation between GNRI scores and mortality rates among cancer patients, encompassing all-cause mortality as well as specific mortality related to both cancerous and non-cancerous causes. The GNRI may be a valuable prognostic tool for predicting cancer mortality outcomes, offering insights that may inform nutritional management and influence the clinical treatment strategies for cancer survivors.

Energy stress-activated AMPK phosphorylates Snail1 and suppresses its stability and oncogenic function.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therapeutic responses and TNBC-related death. However, the underlying mechanisms are not fully understood. In this study, we delineate a previously unrecognized role of aberrant glucose metabolism in regulating the turnover of Snail1, which is a key transcriptional factor of epithelial-mesenchymal transition (EMT) and critically contributes to the acquisition of stemness, metastasis and chemo-resistance. Mechanistically, we demonstrate that AMP-activated protein kinase (AMPK), when activated in response to glucose deprivation, directly phosphorylates Snail1 at Ser11. Such a phosphorylation modification of Snail1 facilitates its recruitment of the E3 ligase FBXO11 and promotes its degradation, thereby suppressing stemness, metastasis and increasing cellular sensitivity to chemotherapies in vitro and in vivo. Clinically, histological analyses reveal a negative correlation between p-AMPKα and Snail1 in TNBC specimens. Taken together, our findings establish a novel mechanism and functional significance of AMPK in linking glucose status to Snail1-dependent malignancies and underscore the potential of AMPK agonists as a promising therapeutic strategy in the management of TNBC.

Highly sensitive and accurate measurement of underivatized phosphoenolpyruvate in plasma and serum via EDTA-facilitated hydrophilic interaction liquid chromatography-tandem mass spectrometry.

Phosphoenolpyruvate (PEP) is an essential intermediate metabolite that is involved in various vital biochemical reactions. However, achieving the direct and accurate quantification of PEP in plasma or serum poses a significant challenge owing to its strong polarity and metal affinity. In this study, a sensitive method for the direct determination of PEP in plasma and serum based on ethylenediaminetetraacetic acid (EDTA)-facilitated hydrophilic interaction liquid chromatography-tandem mass spectrometry was developed. Superior chromatographic retention and peak shapes were achieved using a zwitterionic stationary-phase HILIC column with a metal-inert inner surface. Efficient dechelation of PEP-metal complexes in serum/plasma samples was achieved through the introduction of EDTA, resulting in a significant enhancement of the PEP signal. A PEP isotopically labelled standard was employed as a surrogate analyte for the determination of endogenous PEP, and validation assessments proved the sensitivity, selectivity, and reproducibility of this method. The method was applied to the comparative quantification of PEP in plasma and serum samples from mice and rats, as well as in HepG2 cells, HEK293T cells, and erythrocytes; the results confirmed its applicability in PEP-related biomedical research. The developed method can quantify PEP in diverse biological matrices, providing a feasible opportunity to investigate the role of PEP in relevant biomedical research.

APOBEC3 mutagenesis drives therapy resistance in breast cancer.

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer 1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

Association between life's essential 8 and frailty status among cancer survivors in the United States: a cross-sectional analysis.

BACKGROUND: Frailty not only affects disease survival but also impacts the long-term function and quality life of all adults diagnosed with and/or treated for cancer.The American Heart Association has introduced Life's Essential 8 (LE8) as a novel metric for assessing cardiovascular health. Currently, LE8's application in evaluating the frailty of cancer survivors remains unreported. This research seeks to explore the connection between LE8 scores and frailty levels in cancer survivors across the United States, thereby addressing a significant void in existing studies. METHODS: This study analyzed data from cancer survivors enrolled in the National Health and Nutrition Examination Surveys (NHANES) spanning the years 2005 to 2018, providing a comprehensive dataset. Multivariable logistic regression models were used to examine the linkage between LE8 rankings and frailty condition in cancer survivors. Furthermore, the study delved deeper into this correlation using restricted cubic spline (RCS) curves and subgroup analyses. RESULTS: In the fully adjusted model, an increased LE8 level was closely associated with a reduced odds ratio of frailty among cancer survivors, with an OR of 0.95 (95% CI: 0.94-0.96, p < 0.0001).This pattern persisted across different categorizations of LE8 into low, moderate, and high groups, demonstrating a consistent trend. The analysis revealed a non-linear relationship between LE8 scores and frailty status, further supporting a straightforward association (p-value for non-linearity = 0.0729). CONCLUSION: Studies have found that the higher the LE8 score, the less likely a cancer patient is to develop debilitating symptoms.This indicates that the LE8 scores may provide an opportunity for interventions aimed at improving the prognosis of cancer patients.

Inactivation of cGAS signaling pathway mediated by TDP-43 deficiency protects microglia from hypoxia/reoxygenation induced injury.

BACKGROUND: Microglia are damaged during cerebral ischemia-reperfusion (I/R). This study was performed to investigate the regulatory effect of tAR DNA-binding protein-43 (TDP-43) on microglia after cerebral I/R in vitro and in vivo. METHOD: The hypoxia/reoxygenation (H/R) treated microglia and rats with middle cerebral artery occlusion surgery were constructed respectively. The TDP-43 expression in brain tissues and microglia of each group was evaluated by qPCR and western blotting methods. Cell viability and cell apoptosis were combined to evaluate the degree of cell injury. As for animal experiments, neurological score and infarct volume were obtained to evaluate neurological injury. RESULTS: The levels of TDP-43 in the brain tissues of I/R group were higher than that in sham group. Both TDP-43 and Iba1, a typical microglia marker, were expressed in the brain tissues. TDP-43 was also elevated in microglia with H/R treatment. Inhibition of TDP-43 significantly down-regulated neurological deficit scores of rats after I/R surgery, and weakened the H/R treatment induced injury by promoting cell viability, inhibiting cell apoptosis, down-regulating IL-6 and iNOS levels, and up-regulating Arg-1 and IL-10 levels. Inactivation of cGAS pathway mediated by TDP-43 knockdown protects microglia from H/R treatment induced injury. CONCLUSION: The highly expressed TDP-43 level is associated with cerebral I/R, and inhibition of TDP-43 protects microglia from H/R induced injury through cGAS pathway in vitro and in vivo.

Clinical significance of immune-related antigen CD58 in gliomas and analysis of its potential core related gene clusters.

Background: The clinical significance of immune-related antigen CD58 in gliomas remains uncertain. The aim of this study was to examine the clinical importance and possible core related genes of CD58 in gliomas. Methods: Pan-cancer analysis was to observe the association between CD58 and different tumors, glioma RNA sequencing data and clinical sample analyses were used to observe the relationship between CD58 and glioma, shRNA interference models were to observe the impact of CD58 on glioma cell function, and four glioma datasets and two online analysis platforms were used to explore the core related genes affecting the correlation between CD58 and glioma. Results: High CD58 expression was associated with worse prognosis in various tumors and higher malignancy in glioma. Down regulation of CD58 expression was linked to decreased proliferation, increased apoptosis, and reduced metastasis in glioma cells. The pathways involved in CD58-related effects were enriched for immune cell adhesion and immune factor activation, and the core genes were CASP1, CCL2, IL18, MYD88, PTPRC, and TLR2. The signature of CD58 and its core-related genes showed superior predictive power for glioma prognosis. Conclusion: High CD58 expression is correlated with more malignant glioma types, and also an independent risk factor for mortality in glioma. CD58 and its core-related genes may serve as novel biomarkers for diagnosing and treating glioma.

The secondary visual cortex mediated the enhancement of associative learning on methamphetamine self-administration behaviors.

RATIONALE: Methamphetamine addiction is a persistent and intractable pathological learning and memory, whereas no approved therapeutics is available. However, few attentions have been paid to how associative learning participates in the formation of intractable memory related to drug addiction OBJECTIVES AND METHODS: To investigate the role of associative learning in methamphetamine addiction and the underlying neurobiological mechanism, methamphetamine self-administration, oral sucrose self-administration, chemogenetic neuromanipulation, and fiber photometry in mice were performed in this study. RESULTS: We reported that associative learning increased methamphetamine-induced self-administration, but not oral sucrose self-administration. In addition, the enhancement of methamphetamine-induced self-administration was independent of more methamphetamine consumption, and remained with higher drug-taking and motivation in the absence of visual cues, suggesting the direct effects of the associative learning that enhanced methamphetamine-induced self-administration. Moreover, chemogenetic inactivation of the secondary visual cortex (V2) reduced the enhancement of the drug-taking induced by associative learning but did not alter sucrose-taking. Further fiber photometry of V2 neurons demonstrated that methamphetamine-associative learning elicits V2 neuron excitation, and sucrose-associative learning elicits V2 neuron inhibition. CONCLUSIONS: Therefore, this study reveals the neurobiological mechanism of V2 excitability underlying how associative learning participates in the formation of intractable memory related to drug addiction, and gives evidence to support V2 as a promising target for stimulation therapy for methamphetamine addiction.

Simulating PDT of port-wine stains in the in vivo chicken wattle model using Hemoporfin and radiation at 532 nm: Comparison of a LED and a laser source.

Port-wine stain (PWS) birthmarks are congenital capillary malformations occurring in 0.3 %∼0.5 % of newborns. Hemoporfin-mediated vascular-acting photodynamic therapy (Hemoporfin PDT) is an emerging option for treating PWS. This in vivo study aimed to compare laser and light-emitting diodes (LED) as light source for Hemoporfin PDT. Chicken wattles were used as the animal model. Color and histopathological changes were evaluated after combining Hemoporfin with KTP laser or LED light source of 532 nm at the same doses. Both PDT approaches could induce significant vascular injury and color bleaching. Although the use of the laser resulted in a greater vascular clearance, the LED showed more uniform distribution both in the beam profiles and tissue reaction and exhibited better safety. This in vivo study suggests that the LED is a favorable choice for larger PWS lesion.

Littoral cell angioma of the spleen: A study of 10 cases case series and literature review.

BACKGROUND: Current study aimed to investigate the clinical characterization, differential diagnosis, and treatment of splenic littoral cell angioma (LCA). METHODS: A retrospective analysis was performed for 10 LCA cases admitted to Huzhou Central Hospital from 2007 to 2023, for clinical manifestations, hematological tests, imaging features, pathological features, treatment methods, and prognosis along with the relevant literature was also reviewed. RESULTS: During examinations, no specific clinical manifestations and hematological abnormalities were seen in all 10 cases of LCA. Imaging observations depicted single or even multiple spherical lesions in the spleen. Plains shown by computed tomography (CT) were found somewhat equal or slightly lower in density. On the other hand, magnetic resonance imaging (MRI) plain scans viz. T1 weighted image showed equal low and mixed signals while T2-weighted showed high and low mixed signals. Moreover, punctate low signals could be seen in high signals named "freckle sign" in MRI scans. On contrast-enhanced CT scans, the enhancement of the lesions was not obvious in the arterial phase, and some of the lesions showed edged ring-like enhancements and "filling lake" progressive enhancement during the venous phase and delayed phase. In multiple lesions, the number of enhanced scan lesions showed a variable changing pattern "less-more-less." MRI-enhanced scan showed the characteristics of "fast in and slow out." Microscopic examinations identified tumor tissue actually composed of sinus-like lacunae that anastomosed with each other in the form of a network. Furthermore, cystic expansion and pseudopapillary protrusions were also seen in the dilated sinus cavity which was lined with single-layer endothelial cells having conspicuous cytoplasmic hemosiderin. High immunophenotypic expressions of vascular endothelial cell phenotype (CD31, CD34, FVIII) and tissue cell phenotype (CD68) were also seen. Total and partial splenectomy were performed in 8 and 2 patients, respectively, and follow-up examinations showed survival in all patients with no recurrence. CONCLUSION: LCA is a rare splenic benign lesion with atypical clinical manifestations. CT and MRI imaging are important tools in preoperative diagnosis based on pathomorphological and immunohistochemical examinations. Splenectomy is a superior therapeutic choice with significant impacts and prognosis.

Functionalized chitosan hydrogel promotes osseointegration at the interface of3D printed titanium alloy scaffolds.

Autogenous bone transplantation is a prevalent clinical method for addressing bone defects. However, the limited availability of donor bone and the morbidity associated with bone harvesting have propelled the search for suitable bone substitutes. Bio-inspired scaffolds, particularly those fabricated using electron beam melting (EBM) deposition technology, have emerged as a significant advancement in this field. These 3D-printed titanium alloy scaffolds are celebrated for their outstanding biocompatibility and favorable elastic modulus. Thermosensitive chitosan hydrogel, which transitions from liquid to solid at body temperature, serves as a popular carrier in bone tissue engineering. Icariin (ICA), known for its efficacy in promoting osteoblast differentiation from bone marrow mesenchymal stem cells (BMSCs), plays a crucial role in this context. We developed a system combining a 3D-printed titanium alloy with a thermosensitive chitosan hydrogel, capable of local bone regeneration and integration through ICA delivery. Our in vitro findings reveal that this system can gradually release ICA, demonstrating excellent biocompatibility while fostering BMSC proliferation and osteogenic differentiation. Immunohistochemistry and Micro-CT analyses further confirm the effectiveness of the system in accelerating in vivo bone regeneration and enhancing osseointegration. This composite system lays a significant theoretical foundation for advancing local bone regeneration and integration.

Neuronal activity in the anterior paraventricular nucleus of thalamus positively correlated with sweetener consumption in mice.

Although the brain can discriminate between various sweet substances, the underlying neural mechanisms of this complex behavior remain elusive. This study examines the role of the anterior paraventricular nucleus of the thalamus (aPVT) in governing sweet preference in mice. We fed the mice six different diets with equal sweetness for six weeks: control diet (CD), high sucrose diet (HSD), high stevioside diet (HSSD), high xylitol diet (HXD), high glycyrrhizin diet (HGD), and high mogroside diet (HMD). The mice exhibited a marked preference specifically for the HSD and HSSD. Following consumption of these diets, c-Fos expression levels in the aPVT were significantly higher in these two groups compared to the others. Utilizing fiber photometry calcium imaging, we observed rapid activation of aPVT neurons in response to sucrose and stevioside intake, but not to xylitol or water. Our findings suggest that aPVT activity aligns with sweet preference in mice, and notably, stevioside is the sole plant-based sweetener that elicits an aPVT response comparable to that of sucrose.

Adenoid cystic carcinoma of the Bartholin's gland is underpinned by MYB- and MYBL1- rearrangements.

OBJECTIVE: Adenoid cystic carcinoma (AdCC) of the Bartholin's gland (AdCC-BG) is a very rare gynecologic vulvar malignancy. AdCC-BGs are slow-growing but locally aggressive and are associated with high recurrence rates. Here we sought to characterize the molecular underpinning of AdCC-BGs. METHODS: AdCC-BGs (n = 6) were subjected to a combination of RNA-sequencing, targeted DNA-sequencing, reverse-transcription PCR, fluorescence in situ hybridization (FISH) and MYB immunohistochemistry (IHC). Clinicopathologic variables, somatic mutations, copy number alterations and chimeric transcripts were assessed. RESULTS: All six AdCC-BGs were biphasic, composed of ductal and myoepithelial cells. Akin to salivary gland and breast AdCCs, three AdCC-BGs had the MYB::NFIB fusion gene with varying breakpoints, all of which were associated with MYB overexpression by IHC. Two AdCC-BGs were underpinned by MYBL1 fusion genes with different gene partners, including MYBL1::RAD51B and MYBL1::EWSR1 gene fusions, and showed MYB protein expression. Although the final AdCC-BG studied had MYB protein overexpression, no gene fusion was identified. AdCC-BGs harbored few additional somatic genetic alterations, and only few mutations in cancer-related genes were identified, including GNAQ, GNAS, KDM6A, AKT1 and BCL2, none of which were recurrent. Two AdCC-BGs, both with a MYB::NFIB fusion gene, developed metastatic disease. CONCLUSIONS: AdCC-BGs constitute a convergent phenotype, whereby activation of MYB or MYBL1 can be driven by the MYB::NFIB fusion gene or MYBL1 rearrangements. Our observations further support the notion that AdCCs, irrespective of organ site, constitute a genotypic-phenotypic correlation. Assessment of MYB or MYBL1 rearrangements may be used as an ancillary marker for the diagnosis of AdCC-BGs.

Ultralong Nanowires of Cadmium Phosphate Hydroxide Synthesized Using a Cadmium Oleate Precursor Hydrothermal Method and Sulfidation Conversion to Ultralong CdS Nanowires.

Ultralong nanowires with ultrahigh aspect ratios exhibit high flexibility, and they are promising for applications in various fields. Herein, a cadmium oleate precursor hydrothermal method is developed for the synthesis of ultralong nanowires of cadmium phosphate hydroxide. In this method, water-soluble cadmium salt is used as the cadmium source, water-soluble phosphate is used as the phosphorus source, and sodium oleate is adopted as a reactant to form cadmium oleate precursor and as a structure-directing agent. By using this method, ultralong nanowires of cadmium phosphate hydroxide are successfully synthesized using CdCl2, sodium oleate, and NaH2PO4 as reactants in an aqueous solution by hydrothermal treatment at 180 °C for 24 h. In addition, a new type of flexible fire-resistant inorganic paper with good electrical insulation performance is fabricated using ultralong nanowires of cadmium phosphate hydroxide. As an example of the extended application of this synthetic method, ultralong nanowires of cadmium phosphate hydroxide can be converted to ultralong CdS nanowires through a convenient sulfidation reaction. In this way, ultralong CdS nanowires are successfully synthesized by simple sulfidation of ultralong nanowires of cadmium phosphate hydroxide under mild conditions. The as-prepared ultralong nanowires of cadmium phosphate hydroxide are promising for applications as the precursors and templates for synthesizing other inorganic ultralong nanowires and have wide applications in various fields.

Genomic profiling of primary and metastatic thyroid cancers.

The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs subjected to targeted DNA sequencing, from the cBioPortal database. The cohort included primary and metastatic samples from 276 papillary thyroid carcinomas (PTCs), 5 follicular thyroid carcinomas, 22 Hürthle cell carcinomas (HCCs), 127 poorly differentiated thyroid carcinomas (PDTCs), 30 anaplastic thyroid carcinomas (ATCs) and 15 medullary thyroid carcinomas. The ATCs had the highest tumor mutational burden and the HCCs the highest fraction of the genome altered. Compared to primary PTCs, the metastases had a significantly higher frequency of genetic alterations affecting TERT (51% vs 77%, P < 0.001), CDKN2A (2% vs 10%, P < 0.01), RET (2% vs 7%, P < 0.05), CDKN2B (1% vs 6%, P < 0.05) and BCOR (0% vs 4%, P < 0.05). The distant metastases had a significantly lower frequency of BRAF (64% vs 85%, P < 0.01) and a significantly higher frequency of NRAS (13% vs 3%, P < 0.05) hotspot mutations than the lymph node metastases. Metastases from HCCs and PDTCs were found to be enriched for NF1 (29%) and TP53 (18%) biallelic alterations, respectively. The frequency of subclonal mutations in ATCs was significantly higher than in PTCs (43% vs 25%, P < 0.01) and PDTCs (43% vs 22%, P < 0.01). Metastatic TCs are enriched in clinically informative genetic alterations such as RET translocations, BRAF hotspot mutations and NF1 biallelic losses that may be explored therapeutically.

1064nm Nd:YAG laser promotes chondrocytes regeneration and cartilage reshaping by upregulating local estrogen levels.

Cartilage is frequently used as a scaffolds for repairing and reconstructing body surface organs. However, after successful plastic surgery, transplanted cartilage scaffolds often exhibit deformation and absorption over time. To enhance the shaping stability of cartilage scaffolds and improve patients' satisfaction after reconstructions, we employed the ear folding models in New Zealand rabbits to confirm whether the 1064nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser could promote cartilage reshaping. There was an increase in collagen and aromatase (Cyp19) expression within the ear cartilage after laser treatment. Moreover, we have found that the Cyp19 inhibitor can inhibit the laser's effect on cartilage shaping and reduce collagen and Cyp19 expression. The overall findings suggest that treatment with 1064nm Nd:YAG laser irradiation can enhance estrogen levels in local cartilage tissues by upregulating Cyp19 expression in chondrocytes through photobiomodulation, thereby promoting the proliferation and collagen secretion of chondrocytes to improve cartilage reshaping and stability.

Deubiquitinating enzyme OTUD4 regulates metastasis in triple-negative breast cancer by stabilizing Snail1.

Metastasis is the primary cause of cancer-related deaths and remains poorly understood. Deubiquitinase OTU domain containing 4 (OTUD4) has been reported to regulate antiviral immune responses and resistance to radio- or chemo-therapies in certain cancers. However, the role of OTUD4 in cancer metastasis remain unknown. Here, we demonstrate that the depletion of OTUD4 in triple-negative breast cancer (TNBC) cells markedly suppress cell clonogenic ability, migration, invasion and cancer stem cell population in vitro as well as metastasis in vivo. Mechanistically, the tumor promoting function of OTUD4 is mainly mediated by deuiquitinating and stabilizing Snail1, one key transcriptional factor in the epithelial-mesenchymal transition. The inhibitory effect of targeting OTUD4 could be largely reversed by the reconstitution of Snail1 in OTUD4-deficient cells. Overall, our study establishes the OTUD4-Snail1 axis as an important regulatory mechanism of breast cancer metastasis and provides a rationale for potential therapeutic interventions in the treatment of TNBC.