Structural elucidation a complex galactosyl and glucosyl-rich pectin from the pericarp of immature fruits of Juglans mandshurica Maxim.

A glucosyl-rich pectin, JMMP-3 (Mw, 2.572 × 104 g/mol, O-methyl % = 3.62%), was isolated and purified from the pericarp of the immature fruit of Juglans mandshurica Maxim. (QingLongYi). The structure of JMMP-3 was studied systematically by infrared spectroscopy, monosaccharide compositions, methylation analysis, partial acid hydrolysis, and 1/2D-NMR. The backbone of JMMP-3 possessed a smooth region (→ 4GalA1 →) and a hairy region (→ 4GalA1 → 2Rha1 →) with a molar ratio of 2: 5. The substitution of four characteristic side chains (R1-R4) occurs at C-4 of → 2,4)-α-Rhap-(1→, where R1 is composed of → 5)-α-Araf-(1→, R2 is composed of → 4)-ß-Galp-(1 → and ß-Galp-(1→, R3 is composed of α-Glcp-(1→, →4)-α-Glcp-(1 → and → 4,6)-α-Glcp-(1→, and R4 is composed of → 5)-α-Araf-(1→, ß-Galp-(1→, → 4)-ß-Galp-(1→, → 3,4)-ß-Galp-(1→, → 4,6)-ß-Galp-(1 → and → 2,4)-ß-Galp-(1 → . In addition, the antitumor activity of JMMP-3 on HepG2 cells was preliminarily investigated.

Single cell analyses reveal the PD-1 blockade response-related immune features in hepatocellular carcinoma.

Background: Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy vary a lot. A comparative analysis of the tumor microenvironment (TME) in responders and non-responders is expected to unveil the mechanisms responsible for the immunotherapy resistance and provide potential treatment targets. Methods: We performed sequencing analyses using 10x Genomics technology on six HCC patients who responded to anti-PD-1 therapy and one HCC patient who did not respond. Additionally, we obtained single cell data from untreated, responsive, and nonresponsive HCC patients from public databases, and used part of the datasets as a validation cohort. These data were integrated using algorithms such as Harmony. An independent validation cohort was established. Furthermore, we performed spatial transcriptomic sequencing on the tumor adjacent tissues of three HCC responsive patients using 10x Genomics spatial transcriptomic technology. Additionally, we analyzed data about three HCC patients obtained from public databases. Finally, we validated our conclusions using immunofluorescence, flow cytometry, and in vivo experiments. Results: Our findings confirmed the presence of "immune barrier" partially accounting for the limited efficacy of immunotherapy. Our analysis revealed a significant increase in TREM2+ Macrophages among non-responsive patients expressing multiple immunosuppressive signals. anti-Csf1r monoclonal antibodies effectively eliminated these macrophages and augmented the therapeutic effects of anti-PD-1 therapy. TCR+ Macrophages possessed direct tumor-killing capabilities. IL1B+ cDC2 was the primary functional subtype of cDC2 cells. Absence of THEMIShi CD8+ T subtypes might diminish immunotherapeutic effects. Furthermore, CD8+ T cells entered a state of stress after anti-PD-1 treatment, which might be associated with CD8+ T cell exhaustion and senescence. Conclusions: The profiles of immune TMEs showed differences in HCC patients responsive, non-responsive and untreated. These differences might explain the discounted efficacy of immunotherapy in some HCC patients. The cells and molecules, which we found to carry unique capabilities, may be targeted to enhance immunotherapeutic outcomes in patients with HCC.

Novel genetic alterations in liver cancer distinguish distinct clinical outcomes and combination immunotherapy responses.

Introduction: Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Materials and methods: Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. Results: The genomic landscape exhibited that the most commonly altered genes in HCC were TP53, FAT3, PDE4DIP, KMT2C, FAT1, and MYO18A, while TP53, FAT1, FAT3, PDE4DIP, ROS1, and GALNT11 were frequently altered in ICC; notably, KRAS (18.18% vs. 1.29%) and BAP1 (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that LDLR, MSH2, KDM5D, PDE3A, and FOXO1 were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, p < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered RB1, NOTCH3, MGA, SYNE1, and ZFHX3, as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered LATS1 was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, p < 0.01). Regarding those treated HCC patients, TMB value, altered PTPRZ1, and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but KMT2D alterations were negatively correlated with ORR. In addition, altered KMT2D and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Conclusion: Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.

Exploratory Training for Universal Lesion Detection: Enhancing Lesion Mining Quality Through Temporal Verification.

Universal lesion detection (ULD) has great value in clinical practice as it can detect various lesions across multiple organs. Deep learning-based detectors have great potential but require high-quality annotated training data. In practice, due to cost, expertise requirements, and the diverse nature of lesions, incomplete annotations are often encountered. Directly training ULD detectors under this condition can yield suboptimal results. Leading pseudo-label methods rely on a dynamic lesion-mining mechanism operating at the mini-batch level to address the issue of incomplete annotations. However, the quality of mined lesions in this approach is inconsistent across different iterations, potentially limiting performance enhancement. Inspired by the observation that deep models learn concepts with increasing complexity, we propose an innovative exploratory-training-based ULD (ET-ULD) method to assess the reliability of mined lesions over time. Specifically, we employ a teacher-student detection model, the teacher model is used to mine suspicious lesions, which are combined with incomplete annotations to train the student model. On top of that, we design a bounding-box bank to record the mining timestamps. Each image is trained in several rounds, allowing us to get a sequence of timestamps for the mined lesions. If a mined lesion consistently appears in the timestamp sequence, it is likely to be a true lesion, otherwise, it may just be a noise. This serves as a crucial criterion for selecting reliable mined lesions for subsequent retraining. Our experimental results confirm the effectiveness of ET-ULD, showcasing its ability to surpass existing state-of-the-art methods on two distinct lesion image datasets. Notably, on the DeepLesion dataset, ET-ULD achieved a significant enhancement, outperforming the previous leading method by 5.4% in Average Precision (AP), thus demonstrating its superior performance.

Fluoxetine as a Potential Therapeutic Agent for Inhibiting Melanoma Brain and Lung Metastasis: Induction of Apoptosis, G0/G1 Cell Cycle Arrest, and Disruption of Autophagy Flux.

Brain metastases and lung metastases are major causes of treatment failure and related mortality in melanoma. Fluoxetine hydrochloride (FXT), a widely-used antidepressant, has emerged as a potential anticancer agent in preclinical studies. Previous research has shown its potential to inhibit melanoma. However, its efficacy and the underlying mechanisms in melanoma metastasis, especially concerning brain metastases and lung metastases, remain underexplored. This study investigates FXT's inhibitory effects on melanoma growth and metastasis to the lung and brain. Employing a combination of in vitro assays, we demonstrate FXT's potent suppression of melanoma growth through induction of intrinsic apoptosis, disruption of autophagic flux, and cell cycle arrest at the G0/G1 phase. In in vivo mouse models, we found that FXT exhibits strong inhibitory activity against melanoma brain metastases and lung metastases. Our findings provide a foundation for future clinical exploration of FXT as a novel treatment strategy for melanoma, underscoring its ability to target both primary and metastatic lesions.

Fluorescent Materials Based on Spiropyran for Advanced Anti-Counterfeiting and Information Encryption.

In daily life, counterfeit and substandard products, particularly currency, medicine, food, and confidential documents, are capable of bringing about very serious consequences. The development of anti-counterfeiting and authentication technologies with multilevel securities is a powerful means to overcome this challenge. Among various anti-counterfeiting technologies, fluorescent anti-counterfeiting technology is well-known and commonly used to fight counterfeiters due to its wide material source, low cost, simple usage, good concealment, and simple response mechanism. Spiropyran is favored by scientists in the fields of anti-counterfeiting and information encryption due to its reversible photochromic property. Here, we summarize the current available spiropyran-based fluorescent materials from design to anti-counterfeiting applications. This review will be help scientists to design and develop fluorescent anti-counterfeiting materials with high security, high performance, quick response, and high anti-counterfeiting level.

TriLA: Triple-Level Alignment based Unsupervised Domain Adaptation for Joint Segmentation of Optic Disc and Optic Cup.

Cross-domain joint segmentation of optic disc and optic cup on fundus images is essential, yet challenging, for effective glaucoma screening. Although many unsupervised domain adaptation (UDA) methods have been proposed, these methods can hardly achieve complete domain alignment, leading to suboptimal performance. In this paper, we propose a triple-level alignment (TriLA) model to address this issue by aligning the source and target domains at the input level, feature level, and output level simultaneously. At the input level, a learnable Fourier domain adaptation (LFDA) module is developed to learn the cut-off frequency adaptively for frequency-domain translation. At the feature level, we disentangle the style and content features and align them in the corresponding feature spaces using consistency constraints. At the output level, we design a segmentation consistency constraint to emphasize the segmentation consistency across domains. The proposed model is trained on the RIGA+ dataset and widely evaluated on six different UDA scenarios. Our comprehensive results not only demonstrate that the proposed TriLA substantially outperforms other state-of-the-art UDA methods in joint segmentation of optic disc and optic cup, but also suggest the effectiveness of the triple-level alignment strategy.

Differentiation and immunosuppressive function of CD19+CD24hiCD27+ regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway.

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

Impact of Preoperative Neutrophil to Prealbumin Ratio Index (NPRI) on Short-Term Complications and Long-Term Prognosis in Patients Undergoing Laparoscopic Radical Surgery for Colorectal Cancer.

Objective: This study aims to evaluate the impact and predictive value of the preoperative NPRI on short-term complications and long-term prognosis in patients undergoing laparoscopic radical surgery for colorectal cCancer (CRC). Methods: A total of 302 eligible CRC patients were included, assessing five inflammation-and nutrition-related markers and various clinical features for their predictive impact on postoperative outcomes. Emphasis was on the novel indicator NPRI to elucidate its prognostic and predictive value for perioperative risks. Results: Multivariate logistic regression analysis identified a history of abdominal surgery, prolonged surgical duration, CEA levels ≥5 ng/mL, and NPRI ≥ 3.94 × 10-2 as independent risk factors for postoperative complications in CRC patients. The Clavien--Dindo complication grading system highlighted the close association between preoperative NPRI and both common and severe complications. Multivariate analysis also identified a history of abdominal surgery, tumor diameter ≥5 cm, poorly differentiated or undifferentiated tumors, and NPRI ≥ 2.87 × 10-2 as independent risk factors for shortened overall survival (OS). Additionally, a history of abdominal surgery, tumor maximum diameter ≥5 cm, tumor differentiation as poor/undifferentiated, NPRI ≥ 2.87 × 10-2, and TNM Stage III were determined as independent risk factors for shortened disease-free survival (DFS). Survival curve results showed significantly higher 5-year OS and DFS in the low NPRI group compared to the high NPRI group. The incorporation of NPRI into nomograms for OS and DFS, validated through calibration and decision curve analyses, attested to the excellent accuracy and practicality of these models. Conclusion: Preoperative NPRI independently predicts short-term complications and long-term prognosis in patients undergoing laparoscopic colorectal cancer surgery, enhancing predictive accuracy when incorporated into nomograms for patient survival.

Compound heterozygous with Hb G-Taipei and Hb Lepore-Boston-Washington: An unexpected finding triggered by HbA1c measurement.

Background: Hemoglobin A1c has been widely used to diagnose and monitor diabetes. However, the accuracy of HbA1c analysis can be significantly affected by hemoglobin variants, leading to falsely low or elevated levels and misdiagnosis or inappropriate diabetes management. Case report: In this study, we present the case of a 23-year-old man with undetectable HbA1c levels during his annual checkup by high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE). To investigate the reason for HbA1c absence, Sanger sequencing, multiplex ligation-dependent probe amplification assay (MLPA), long-read single molecule real-time sequencing (SMRT) and MALDI-TOF mass spectrometry (MS) were performed, and the proband was identified as compound heterozygous of ß-thalassemia with Hb G-Taipei (HBB:c.68A > G) and Hb Lepore-Boston-Washington (NG_000007.3:g.63632_71046del). Conclusion: The combination of these molecular technologies including MLPA, long-read SMRT sequencing and MALDI-TOF MS is beneficial for identifying rare hemoglobin variants. This case also provides essential evidence for uncovering the effect of compound heterozygosity for Hb Lepore-Boston-Washington and Hb G-Taipei on hematological phenotypes and HbA1c analysis.

Neutrophil-to-lymphocyte ratio in colorectal tissue affects prognosis in patients with colorectal cancer.

The objective of this investigation was to analyse the correlation between the neutrophil-to-lymphocyte ratio (NLR) status in the immune microenvironment (IME) and the prognostic outcomes of patients who have undergone radical surgery for colorectal cancer (CRC). In light of the continued prevalence of CRC in China, this study utilised Kaplan-Meier and Cox regression analyses to assess the prognostic relevance of NLR status in IME among patients with CRC. Furthermore, cellular experiments, such as cell scratching, were conducted to elucidate the underlying mechanisms of NLR's impact on CRC. The NLR status in IME has been found to have a significant impact on the prognosis of patients with CRC. Patients who exhibit elevated intratumoural and extratumoural NLR are associated with a poor prognosis. Experimental evidence indicates that tumour-associated neutrophil (TAN) augments the migratory, invasive, and proliferative potential of HT-29, HCT-116 and LOVO colorectal cancer cells, while concurrently reducing their sensitivity to oxaliplatin. Conversely, lymphocytes have demonstrated cytotoxic effects on HT-29 cells. The NLR status in IME may serve as a prognostic biomarker for resectable CRC.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

A case report of a patient with Turner syndrome who develops catatonia secondary to psychotic symptoms.

RATIONALE: Turner syndrome (TS) is a genetic disorder associated with partial or complete monosomy X abnormalities; some patients may have a higher risk of psychiatric symptoms. Catatonia is associated with a wide range of life-threatening complications with complex pathogenesis; However, It very rare for patients with TS to develop psychotic symptoms and eventually progress to catatonia. This case report describes the diagnostic and therapeutic course of catatonia-associated TS. PATIENT CONCERNS: In this study, we report the case of a patient with TS who initially developed sudden hallucinations, delusions, and emotional instability, followed by catatonia. DIAGNOSES: The patient was diagnosed with: unspecified catatonia; TS. INTERVENTIONS: Treatment included administering a combination of esazolam injections and olanzapine tablets, placing a gastric tube and urinary catheter, and providing nutritional support. OUTCOMES: After treatment, the patient's hallucinations, delusions, and catatonia disappeared, with no residual sequelae, and social functioning returned to normal. LESSONS: For patients with TS who present with psychotic symptoms and catatonia, a comprehensive evaluation is necessary, and treatment with antipsychotics and benzodiazepines is effective.

The Influence of Exercise on Cancer Risk, the Tumor Microenvironment and the Treatment of Cancer.

There are several modifiable factors that can be targeted to prevent and manage the occurrence and progression of cancer, and maintaining adequate exercise is a crucial one. Regular physical exercise has been shown to be a beneficial strategy in preventing cancer, potentially amplifying the effectiveness of established cancer therapies, alleviating certain cancer-related symptoms, and possibly mitigating side effects resulting from treatment. Nevertheless, the exact mechanisms by which exercise affects tumors, especially its impact on the tumor microenvironment (TME), remain uncertain. This review aims to present an overview of the beneficial effects of exercise in the context of cancer management, followed by a summary of the exercise parameters, especially exercise intensity, that need to be considered when prescribing exercise for cancer patients. Finally, we discuss the influence of exercise on the TME, including its effects on crucial immune cells (e.g., T cells, macrophages, neutrophils, natural killer cells, myeloid-derived suppressor cells, B cells), intratumor angiogenesis, and cancer metabolism. This comprehensive review provides up-to-date scientific evidence on the effects of exercise training on cancer and offers guidance to clinicians for the development of safe and feasible exercise training programs for cancer patients in clinical practice.

Antipsychotic Zuclopenthixol Inhibits Melanoma Growth and Brain Metastasis by Inducing Apoptosis and Cell Cycle Arrest.

BACKGROUND: The incidence of melanoma brain metastasis (MBM) is high and significantly compromises patient survival and quality of life. Effective treatment of MBM is made difficult by the blood-brain barrier (BBB), since it restricts the entry of drugs into the brain. Certain anti-psychotic drugs able to cross the BBB have demonstrated efficacy in suppressing brain metastasis in preclinical studies. However, the activity of zuclopenthixol against MBM is not yet clear. METHODS: Cell viability assays were employed to investigate the potential of zuclopenthixol in the treatment of MBM. Subsequently, the mechanism of action was investigated by RNA-sequencing (RNAseq), flow cytometry-based cell cycle and apoptosis assays, protein expression analysis, and autophagy flux detection. Additionally, the efficacy of zuclopenthixol against tumor growth was investigated in vivo, including MBM models. RESULTS: Zuclopenthixol inhibited the proliferation of various melanoma cell lines at minimal doses by causing cell cycle arrest in the G0/G1 phase and mitochondrial-mediated intrinsic apoptosis. Zuclopenthixol also induced cytoprotective autophagy, and inhibition of autophagy enhanced the anti-melanoma effects of zuclopenthixol. Furthermore, zuclopenthixol inhibited the growth of human melanoma tumors in nude mice, as well as the growth of intracranial metastases in a mouse model of MBM. CONCLUSIONS: These results demonstrate that zuclopenthixol has significant potential as an effective therapeutic agent for MBM.

Remote Radical Azidation of Unactivated C(sp3)-H Bonds in Sulfamoyl Azides.

An efficient method for remote radical C(sp3)-H azidation at unactivated sites is described. C-H functionalization proceeds via intramolecular 1,5-hydrogen atom transfer to N-centered radicals that are generated via azido group transfer and/or fragmentation. The readily installed sulfamoyl azide serves as both an amidyl radical precursor and an azido source. This reaction features excellent site selectivity for tertiary, secondary, primary, and benzylic C(sp3)-H bonds and exhibits broad functional group compatibility.

Learning-enabled data transmission with up to 32 multiplexed orbital angular momentum channels through a commercial multi-mode fiber.

Multiplexing orbital angular momentum (OAM) modes enable high-capacity optical communication. However, the highly similar speckle patterns of adjacent OAM modes produced by strong mode coupling in common fibers prevent the utility of OAM channel demultiplexing. In this paper, we propose a machine learning-supported fractional OAM-multiplexed data transmission system to sort highly scattered data from up to 32 multiplexed OAM channels propagating through a commercial multi-mode fiber parallelly with an accuracy of >99.92%, which is the largest bit number of OAM superstates reported to date (to the best of our knowledge). Here, by learning limited samples, unseen OAM superstates during the training process can be predicted precisely, which reduces the explosive quantity of the dataset. To verify its application, both gray and colored images, encoded by the given system, have been successfully transmitted with error rates of <0.26%. Our work might provide a promising avenue for high-capacity OAM optical communication in scattering environments.

Inhibition of TNBC Cell Growth by Paroxetine: Induction of Apoptosis and Blockage of Autophagy Flux.

The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use.

Fundamental probing limit on the high-order orbital angular momentum of light.

The orbital angular momentum (OAM) of light, possessing an infinite-dimensional degree of freedom, holds significant potential to enhance the capacity of optical communication and information processing in both classical and quantum regimes. Despite various methods developed to accurately measure OAM modes, the probing limit of the highest-order OAM remains an open question. Here, we report an accurate recognition of superhigh-order OAM using a convolutional neural network approach with an improved ResNeXt architecture, based on conjugated interference patterns. A type of hybrid beam carrying double OAM modes is utilized to provide more controllable degrees of freedom for greater recognition of the OAM modes. Our contribution advances the OAM recognition limit from manual counting to machine learning. Results demonstrate that, within our optical system, the maximum recognizable OAM modes exceed l = ±690 with an accuracy surpassing 99.93%, the highest achieved by spatial light modulator to date. Enlarging the active area of the CCD sensor extends the number of recognizable OAM modes to 1300, constrained only by the CCD resolution limit. Additionally, we explore the identification of fractional high-order OAM modes with a resolution of 0.1 from l = ±600.0 to l = ±600.9, achieving a high accuracy of 97.86%.

Discovery of anticancer function of Febrifugine: Inhibition of cell proliferation, induction of apoptosis and suppression steroid synthesis in bladder cancer cells.

Bladder cancer is a prevalent malignancy affecting the urinary system, which presents a significant global health concern. Although there are many treatments for bladder cancer, identifying more effective drugs and methods remains an urgent problem. As a pivotal component of contemporary medical practice, traditional Chinese medicine (TCM) assumes a crucial role in the realm of anti-tumor therapy, especially with the identification of active ingredients and successful exploration of pharmacological effects. Febrifugine, identified as a quinazoline-type alkaloid compound extracted from the Cytidiaceae family plant Huangchangshan, exhibits heightened sensitivity to bladder cancer cells in comparison to control cells (non-cancer cells) group. The proliferation growth of bladder cancer cells T24 and SW780 was effectively inhibited by Febrifugine, and the IC50 was 0.02 and 0.018 µM respectively. Febrifugine inhibits cell proliferation by suppressing DNA synthesis and induces cell death by reducing steroidogenesis and promoting apoptosis. Combined with transcriptome analysis, Febrifugine was found to downregulate low density lipoprotein receptor-associated protein, lanosterol synthase, cholesterol biosynthesis second rate-limiting enzyme, 7-dehydrocholesterol reductase, flavin adenine dinucleotide dependent oxidoreductase and other factors to inhibit the production of intracellular steroids in bladder cancer T24 cells. The results of animal experiments showed that Febrifugine could inhibit tumor growth. In summary, the effect of Febrifugine on bladder cancer is mainly through reducing steroid production and apoptosis. Therefore, this study contributes to the elucidation of Febrifugine's potential as an inhibitor of bladder cancer and establishes a solid foundation for the future development of novel therapeutic agents targeting bladder cancer.