Rare Earth Nanoprobes for Targeted Delineation of Triple Negative Breast Cancer and Enhancement of Radioimmunotherapy.

Radiotherapy demonstrates a synergistic effect with immunotherapy by inducing a transformation of "immune cold" tumors into "immune hot" tumors in triple negative breast cancer (TNBC). Nevertheless, the effectiveness of immunotherapy is constrained by low expression of tumor-exposed antigens, inadequate inflammation, and insufficient tumor infiltrating lymphocyte (TILs). To address this predicament, novel lutecium-based rare earth nanoparticles (RENPs) are synthesized with the aim of amplifying radiation effect and tumor immune response. The nanoprobe is characterized by neodymium-based down-conversion fluorescence, demonstrating robust photostability, biocompatibility, and targetability. The conjugation of RENPs with a CXCR4 targeted drug enables precise delineation of breast tumors using a near-infrared imaging system and improves radiation efficacy via lutetium-based radio-sensitizer in vivo. Furthermore, the study shows a notable enhancement of immune response through the induction of immunogenic cell death and recruitment of TILs, resulting in the inhibition of tumor progression both in vitro and in vivo models following the administration of nanoparticles. Hence, the novel multifunctional nanoprobes incorporating various lanthanide elements offer the potential for imaging-guided tumor delineation, radio-sensitization, and immune activation post-radiation, thus presenting an efficient radio-immunotherapeutic approach for TNBC.

Nomogram prediction of vessels encapsulating tumor clusters in small hepatocellular carcinoma ≤ 3 cm based on enhanced magnetic resonance imaging.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) represent a recently discovered vascular pattern associated with novel metastasis mechanisms in hepatocellular carcinoma (HCC). However, it seems that no one have focused on predicting VETC status in small HCC (sHCC). This study aimed to develop a new nomogram for predicting VETC positivity using preoperative clinical data and image features in sHCC (≤ 3 cm) patients. AIM: To construct a nomogram that combines preoperative clinical parameters and image features to predict patterns of VETC and evaluate the prognosis of sHCC patients. METHODS: A total of 309 patients with sHCC, who underwent segmental resection and had their VETC status confirmed, were included in the study. These patients were recruited from three different hospitals: Hospital 1 contributed 177 patients for the training set, Hospital 2 provided 78 patients for the test set, and Hospital 3 provided 54 patients for the validation set. Independent predictors of VETC were identified through univariate and multivariate logistic analyses. These independent predictors were then used to construct a VETC prediction model for sHCC. The model's performance was evaluated using the area under the curve (AUC), calibration curve, and clinical decision curve. Additionally, Kaplan-Meier survival analysis was performed to confirm whether the predicted VETC status by the model is associated with early recurrence, just as it is with the actual VETC status and early recurrence. RESULTS: Alpha-fetoprotein_lg10, carbohydrate antigen 199, irregular shape, non-smooth margin, and arterial peritumoral enhancement were identified as independent predictors of VETC. The model incorporating these predictors demonstrated strong predictive performance. The AUC was 0.811 for the training set, 0.800 for the test set, and 0.791 for the validation set. The calibration curve indicated that the predicted probability was consistent with the actual VETC status in all three sets. Furthermore, the decision curve analysis demonstrated the clinical benefits of our model for patients with sHCC. Finally, early recurrence was more likely to occur in the VETC-positive group compared to the VETC-negative group, regardless of whether considering the actual or predicted VETC status. CONCLUSION: Our novel prediction model demonstrates strong performance in predicting VETC positivity in sHCC (≤ 3 cm) patients, and it holds potential for predicting early recurrence. This model equips clinicians with valuable information to make informed clinical treatment decisions.

Emodin alleviates intestinal ischemia/reperfusion-induced lung injury by upregulating HO-1 expression via PI3K/AkT pathway.

BACKGROUND: Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs, has been proved to be an effective therapeutic agent in the treatment of many diseases. However, its effect on lung injury after intestinal ischemia/reperfusion injury remains unknown. This research was designed to investigate whether emodin protects against intestinal ischemia/reperfusion-induced lung injury and to elucidate the underlying molecular mechanisms in vivo and in vitro. METHODS: Intestinal ischemia/reperfusion injury was induced by occluding the superior mesenteric artery in mice, and mouse lung epithelial-12 cells were subjected to oxygen-glucose deprivation and reoxygenation to establish an in vitro model. RESULTS: Our data indicated that emodin treatment reduced intestinal ischemia/reperfusion-induced oxidative stress, inflammation and apoptosis in lung tissues and alleviated lung injury. However, the protective effects of emodin on intestinal ischemia/reperfusion-induced lung injury were reversed by the protein kinase B inhibitor triciribine or the heme oxygenase-1 inhibitor tin protoporphyrin IX. The protein kinase inhibitor triciribine also downregulated the expression of heme oxygenase-1. CONCLUSION: In conclusion, our data suggest that emodin treatment protects against intestinal ischemia/reperfusion-induced lung injury by enhancing heme oxygenase-1 expression via activation of the PI3K/protein kinase pathway. Emodin may act as a potential therapeutic agent for the prevention and treatment of lung injury induced by intestinal ischemia/reperfusion.

P4HA2 contributes to head and neck squamous cell carcinoma progression and EMT through PI3K/AKT signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) can be defined as a deadly illness with a dismal prognosis in advanced stages. Therefore, we seek to examine P4HA2 expression and effect in HNSCC, along with the underlying mechanisms. This study utilized integrated bioinformatics analyses to evaluate the P4HA2 expression pattern, prognostic implication, and probable function in HNSCC. The study conducted various in vitro experiments, including colony formation, CCK-8, flow cytometry, wound healing, and transwell assays, on the human HNSCC cell line CAL-27 to examine the involvement of P4HA2 in HNSCC progression. Moreover, western blotting was used to investigate epithelial-mesenchymal transition (EMT) markers and PI3K/AKT pathway markers to elucidate the underlying mechanisms. P4HA2 expression was significantly enhanced in HNSCC, and its overexpression was correlated to tumor aggressiveness and a poor prognosis in patients. Based on in vitro experiments, the overexpressed P4HA2 enhanced cell proliferation, migration, invasion, as well as EMT while reducing apoptosis, whereas P4HA2 silencing exhibited the reverse effect. P4HA2 overexpression enhanced PI3K/AKT phosphorylation in HNSCC cells. Moreover, LY294002 was observed to counteract the effects of upregulated P4HA2 on proliferation, migration, invasion, and EMT in HNSCC. Collectively, we indicated that P4HA2 promoted HNSCC progression and EMT via PI3K/AKT signaling pathway.

Cell-free biosynthesis and engineering of ribosomally synthesized lanthipeptides.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products with diverse chemical structures and potent biological activities. A vast majority of RiPP gene clusters remain unexplored in microbial genomes, which is partially due to the lack of rapid and efficient heterologous expression systems for RiPP characterization and biosynthesis. Here, we report a unified biocatalysis (UniBioCat) system based on cell-free gene expression for rapid biosynthesis and engineering of RiPPs. We demonstrate UniBioCat by reconstituting a full biosynthetic pathway for de novo biosynthesis of salivaricin B, a lanthipeptide RiPP. Next, we delete several protease/peptidase genes from the source strain to enhance the performance of UniBioCat, which then can synthesize and screen salivaricin B variants with enhanced antimicrobial activity. Finally, we show that UniBioCat is generalizable by synthesizing and evaluating the bioactivity of ten uncharacterized lanthipeptides. We expect UniBioCat to accelerate the discovery, characterization, and synthesis of RiPPs.

Labeling and Diagnostic Value of miRNA-28-3p in Patients with Nasopharyngeal Carcinoma.

Objective: To explore how miRNA-28-3p targets BIN1 and affects the biological behavior of nasopharyngeal carcinoma cells, and to evaluate its potential as a predictive biomarker for NPC. Methods: We studied 100 nasopharyngeal carcinoma patients who underwent surgery between January 2021 and January 2022. Tissues from tumors and adjacent normal areas were analyzed. Participants were categorized into two groups: one with nasopharyngeal carcinoma and another with adjacent normal tissue. Additionally, the nasopharyngeal carcinoma cell line CNE-2 was divided into three groups: an untreated control, a negative control with NC plasmid, and a test group treated with a miRNA-28-3p inhibitor. Key techniques included PCR, Western blotting, CCK-8, flow cytometry, focusing on the interactions between miRNA-28-3p and BIN1 and their predictive significance for NPC. Results: miRNA-28-3p levels were significantly higher in nasopharyngeal carcinoma tissues compared to adjacent normal tissues (P < .05). The predictive performance of miRNA-28-3p for NPC featured an AUC > 0.75 with sensitivity and specificity both exceeding 70% (P < .001). In nasopharyngeal carcinoma cells, miRNA-28-3p levels were significantly elevated compared to normal cells (P < .05). Transfection with the miRNA-28-3p inhibitor increased apoptosis and BIN1 protein levels while reducing cell proliferation, invasion, and migration significantly (P < .05). Conclusion: miRNA-28-3p is overexpressed in nasopharyngeal carcinoma and inhibits tumor cell proliferation, migration, and invasion, while promoting apoptosis by targeting BIN1. The level of miRNA-28-3p expression serves as a sensitive indicator for predicting nasopharyngeal carcinoma, affirming its potential as a diagnostic biomarker and underscoring the significance of these findings in enhancing understanding and clinical management of NPC.

Synchronous papillary and follicular thyroid carcinomas: the first retrospective cohort study and literature review.

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) contribute to more than 95% of thyroid malignancies. However, synchronous PTC and FTC are less common; it is most commonly discovered incidentally as synchronous malignancies during operation, which adds difficulties to intraoperative decision-making and postoperative treatment. Therefore, we analyzed the clinicopathological characteristics and prognosis of patients with PTC and FTC in our center. Methods: We conducted a search of single PTC, single FTC, and synchronous PTC/FTC patients who received initial surgery treatment at Fudan University Shanghai Cancer Center from 2006 to 2018 and collected paraffin-embedded samples of synchronous patients. Clinicopathological characteristics were collected from the electronic medical record system. Follow-up was performed through telephone contact or medical records. Exome sequencing was performed by ThyroLead panel. Results: Total of 42 synchronous PTC/FTC patients, 244 single FTC patients, and 2,959 single PTC patients were included. It showed a similarity between the clinicopathological features of synchronous thyroid cancer patients and single PTC patients, with a greater proportion of females, higher probabilities of lymph node metastasis, and higher rate of concurrence of Hashimoto's disease. The disease-free survival (DFS) curve indicated a worse prognosis of the synchronous group and single PTC group compared to the single FTC group, who had a propensity for neck lymph node recurrence; however, logistic multivariate regression analysis did not find any factor related to recurrence in the synchronous group. After re-checking pathology, DNA extraction, and quality control, genetic alteration information of 62 samples including primary tumors and metastatic lymph nodes from 35 synchronous cancer patients was displayed. In total, 81 mutations and 1 fusion gene were identified, including mutations related to outcomes and targeted therapy. Besides, some rare mutations in thyroid cancer were found in these patients. Conclusions: To conclude, synchronous PTC/FTC tend to be incidentally discovered during or after operation, behaving more like single PTC. The prognosis of synchronous patients is worse than that of single FTC patients and supplemental cervical lymph node dissection, total thyroidectomy, and postoperative radioiodine therapy should be taken into consideration after diagnosis. The next-generation sequencing (NGS) showed a unique molecular feature of synchronous patients with some rare mutations.

Rapid and Visual Detection of Volatile Amines Based on Their Gas-Solid Reaction with Tetrachloro-p-Benzoquinone.

The detection of volatile amines is necessary due to the serious toxicity hazards they pose to human skin, respiratory systems, and nervous systems. However, traditional amines detection methods require bulky equipment, high costs, and complex measurements. Herein, we report a new simple, rapid, convenient, and visual method for the detection of volatile amines based on the gas-solid reactions of tetrachloro-p-benzoquinone (TCBQ) and volatile amines. The gas-solid reactions of TCBQ with a variety of volatile amines showed a visually distinct color in a time-dependent manner. Moreover, TCBQ can be easily fabricated into simple and flexible rapid test strips for detecting and distinguishing n-propylamine from other volatile amines, including ethylamine, n-butyamine, n-pentamine, n-butyamine and dimethylamine, in less than 3 s without any equipment assistance.

Prognostic value of preoperative radiographic perinephric fat features in renal cell carcinoma patients undergoing surgery.

BACKGROUND: We aimed to assess the prognostic importance of perinephric fat features in images of patients with non-metastatic renal cell carcinoma (RCC) undergoing surgery. METHODS: We enrolled RCC patients who underwent surgical treatment between 2011 and 2019. Two characteristics, including perinephric fat thickness and perinephric fat stranding, were evaluated using preoperative computed tomography or magnetic resonance images. The association between perinephric fat characteristics and disease progression was examined by Kaplan-Meier survival analysis and Cox regression model. RESULTS: In a multivariate Cox proportional hazards model adjusting for tumor stage, intratumoral necrosis, and neutrophil-to-lymphocyte ratio, we found that patients in the thin perinephric fat group (<1 cm) had a poorer progression-free survival (PFS) compared to the thick perinephric fat group (≥1 cm) (HR 2.8; 95% CI 1.175-6.674, p = 0.02). Additionally, the fat stranding group had a poorer PFS than the non-stranding group (HR 3.852; 95% CI 1.082-13.704, p = 0.037). The non-stranding with thick perinephric fat group exhibits the highest cumulative PFS while the stranding with thin perinephric fat group has the lowest cumulative PFS. In receiver operating characteristic curve analysis, combing these two perinephric fat characteristics with tumor stage can achieve a better discriminatory power than tumor stage alone. CONCLUSIONS: Our study indicates that the evaluation of image-based perinephric fat features is a simple, straightforward, reproducible tool for predicting RCC prognosis and may assist in preoperative risk stratification.

Synergistic enhancement of the mouse Pramex1 and Pramel1 in repressing retinoic acid (RA) signaling during gametogenesis.

BACKGROUND: PRAME constitutes one of the largest multi-copy gene families in Eutherians, encoding cancer-testis antigens (CTAs) with leucine-rich repeats (LRR) domains, highly expressed in cancer cells and gametogenic germ cells. This study aims to elucidate genetic interactions between two members, Pramex1 and Pramel1, in the mouse Prame family during gametogenesis using a gene knockout approach. RESULT: Single-gene knockout (sKO) of either Pramex1 or Pramel1 resulted in approximately 7% of abnormal seminiferous tubules, characterized by a Sertoli-cell only (SCO) phenotype, impacting sperm count and fecundity significantly. Remarkably, sKO female mice displayed normal reproductive functions. In contrast, Pramex1/Pramel1 double knockout (dKO) mice exhibited reduced fecundity in both sexes. In dKO females, ovarian primary follicle count decreased by 50% compared to sKO and WT mice, correlating with a 50% fecundity decrease. This suggested compensatory roles during oogenesis in Pramex1 or Pramel1 sKO females. Conversely, dKO males showed an 18% frequency of SCO tubules, increased apoptotic germ cells, and decreased undifferentiated spermatogonia compared to sKO and WT testes. Western blot analysis with PRAMEX1- or PRAMEL1-specific antibodies on sKO testes revealed compensatory upregulation of each protein (30-50%) in response to the other gene's deletion. Double KO males exhibited more severe defects in sperm count and litter size, surpassing Pramex1 and Pramel1 sKO accumulative effects, indicating a synergistic enhancement interaction during spermatogenesis. Additional experiments administering trans-retinoic acid (RA) and its inhibitor (WIN18,446) in sKO, dKO, and WT mice suggested that PRAMEX1 and PRAMEL1 synergistically repress the RA signaling pathway during spermatogenesis. CONCLUSION: Data from sKO and dKO mice unveil a synergistic interaction via the RA signaling pathway between Pramex1 and Pramel1 genes during gametogenesis. This discovery sets the stage for investigating interactions among other members within the Prame family, advancing our understanding of multi-copy gene families involved in germ cell formation and function.

[Effect of Chlorambucil Combined with Ibrutinib on Mantle Cell Lymphoma Cell Line Jeko-1 and Its Related Mechanism].

OBJECTIVE: To investigate the toxic effect of chlorambucil combined with ibrutinib on mantle cell lymphoma (MCL) cell line Jeko-1 and its related mechanism. METHODS: The MCL cell line Jeko-1 was incubated with different concentrations of chlorambucil or ibrutinib or the combination of the two drugs, respectively. CCK-8 assay was used to detect the proliferation of the cells, and Western blot was used to measure the protein expression levels of BCL-2, caspase-3, PI3K, AKT and P-AKT. RESULTS: After Jeko-1 cells were treated with chlorambucil (3.125, 6.25, 12.5, 25, 50 µmol/L) and ibrutinib (3.125, 6.25, 12.5, 25, 50 µmol /L) alone for 24, 48, 72h respectively, the cell proliferation was inhibited in a time- and dose-dependent manner. Moreover, the two drugs were applied in combination at low doses (single drug inhibition rate<50%), and the results showed that the combination of two drugs had a more significant inhibitory effect (all P < 0.05). Compared with the control group, the apoptosis rate of the single drug group of chlorambucil (3.125, 6.25, 12.5, 25, 50 µmol/L) and ibutinib (3.125, 6.25, 12.5, 25, 50 µmol/L) was increased in a dose-dependent manner. The combination of the two drugs at low concentrations (3.125, 6.25, 12.5 µmol/L) could significantly increase the apoptosis rate compared with the corresponding concentration of single drug groups (all P < 0.05). Compared with control group, the protein expression levels of caspase-3 in Jeko-1 cells were upregulated, while the protein expression levels of BCL-2, PI3K, and p-AKT/AKT were downregulated after treatment with chlorambucil or ibrutinib alone. The combination of the two drugs could produce a synergistic effect on the expressions of the above-mentioned proteins, and the differences between the combination group and the single drug groups were statistically significant (all P < 0.05). CONCLUSION: Chlorambucil and ibrutinib can promote the apoptosis of MCL cell line Jeko-1, and combined application of the two drugs shows a synergistic effect, the mechanism may be associated with the AKT-related signaling pathways.

Radiomics of Preoperative Multi-Sequence Magnetic Resonance Imaging Can Improve the Predictive Performance of Microvascular Invasion in Hepatocellular Carcinoma.

Background: The aim of the study is to demonstrate that radiomics of preoperative multi-sequence magnetic resonance imaging (MRI) can indeed improve the predictive performance of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). Methods: A total of 206 patients with pathologically confirmed HCC who underwent preoperative enhanced MRI were retrospectively recruited. Univariate and multivariate logistic regression analysis identified the independent clinicoradiologic predictors of MVI present and constituted the clinicoradiologic model. Recursive feature elimination (RFE) was applied to select radiomics features (extracted from six sequence images) and constructed the radiomics model. Clinicoradiologic model plus radiomics model formed the clinicoradiomics model. Five-fold cross-validation was used to validate the three models. Discrimination, calibration, and clinical utility were used to evaluate the performance. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to compare the prediction accuracy between models. Results: The clinicoradiologic model contained alpha-fetoprotein (AFP)_lg10, radiological capsule enhancement, enhancement pattern and arterial peritumoral enhancement, which were independent risk factors of MVI. There were 18 radiomics features related to MVI constructed the radiomics model. The mean area under the receiver operating curve (AUC) of clinicoradiologic, radiomics and clinicoradiomics model were 0.849, 0.925 and 0.950 in the training cohort and 0.846, 0.907 and 0.933 in the validation cohort, respectively. The three models' calibration curves fitted well, and decision curve analysis (DCA) confirmed the clinical usefulness. Compared with the clinicoradiologic model, the NRI of radiomics and clinicoradiomics model increased significantly by 0.575 and 0.825, respectively, and the IDI increased significantly by 0.280 and 0.398, respectively. Conclusions: Radiomics of preoperative multi-sequence MRI can improve the predictive performance of MVI in HCC.

Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

A highly reversible force-assisted Li - CO2 battery based on piezoelectric effect of Bi0.5Na0.5TiO3 nanorods.

The use of light-assisted cathode is regarded as an effective approach to reduce the overpotential of lithium carbon dioxide (Li - CO2) batteries. However, the inefficient electron-hole separation and the complex discharge-charge reactions hamper the efficiency of CO2 photocatalytic reaction in battery. Herein, a highly reversible force-assisted Li - CO2 battery has been established for the first time by employing a Bi0.5Na0.5TiO3 nanorods piezoelectric cathode. The high-energy electron and holes generated by the piezoelectric cathode with ultrasonic force can effectively enhance the carbon dioxide reduction reaction (CDRR) and carbon dioxide evolution reaction (CDER) kinetics, thereby reducing the overpotentials during the discharge-charge processes. Moreover, the morphology of the discharge product (Li2CO3) can be modified via the dense surface electrons of the piezoelectric cathode, resulting in the promoted decomposition kinetics of Li2CO3 in charging progress. Thus, the force-assisted Li - CO2 battery with the unique piezoelectric cathode can adjust the output and input energy by ultrasonic wave, and provides an ultra-low charging platform of 3.52 V, and exhibits excellent cycle stability (a charging platform of 3.42 V after 100 h cycles). The investigation of the force-assisted process described herein provides significant insights to solve overpotential in the Li - CO2 batteries system.

Mycobacteriaceae Phenome Atlas (MPA): A Standardized Atlas for the Mycobacteriaceae Phenome Based on Heterogeneous Sources.

The bacterial family Mycobacteriaceae includes pathogenic and nonpathogenic bacteria, and systematic research on their genome and phenome can give comprehensive perspectives for exploring their disease mechanism. In this study, the phenotypes of Mycobacteriaceae were inferred from available phenomic data, and 82 microbial phenotypic traits were recruited as data elements of the microbial phenome. This Mycobacteriaceae phenome contains five categories and 20 subcategories of polyphasic phenotypes, and three categories and eight subcategories of functional phenotypes, all of which are complementary to the existing data standards of microbial phenotypes. The phenomic data of Mycobacteriaceae strains were compiled by literature mining, third-party database integration, and bioinformatics annotation. The phenotypes were searchable and comparable from the website of the Mycobacteriaceae Phenome Atlas (MPA, https://www.biosino.org/mpa/). A topological data analysis of MPA revealed the co-evolution between Mycobacterium tuberculosis and virulence factors, and uncovered potential pathogenicity-associated phenotypes. Two hundred and sixty potential pathogen-enriched pathways were found by Fisher's exact test. The application of MPA may provide novel insights into the pathogenicity mechanism and antimicrobial targets of Mycobacteriaceae. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00101-5.

Quinolines: A Promising Heterocyclic Scaffold for Cancer Therapeutics.

The quinoline scaffold is a widely recognized heterocycle with applications across various disease categories, ranging from malaria and viral infections to bacterial infections, high cholesterol, and even tumors. Consequently, quinoline plays a crucial role in the development of new drugs, and the field greatly benefits from advancements in computer-aided drug design. This review aims to provide insights into the evolution of quinoline and its derivatives, offering a comprehensive exploration of both marketed and developing drugs. Furthermore, the function and mechanism of quinoline compounds are introduced. Many studies rely on cell experiments to demonstrate drug cytotoxicity. In the concluding section of this review, the interaction between quinoline compounds and targets is simulated using computer-aided drug design methods. A thorough analysis is conducted on the potential influencing factors affecting the binding state between quinoline compounds and targets. Notably, the Pi-Alkyl interaction emerges as a significant contributor, while hydrogen bonding is identified as a pivotal bond in these interactions. This review serves as a valuable overview of the potential contributions of quinoline compounds to cancer treatment. It seamlessly combines the essential functions of marketed quinoline drugs with the promise held by emerging quinoline-based compounds. Additionally, the simulation of interactions between quinoline compounds and proteins through computer-aided design enhances our understanding of these compounds' efficacy.

Constructing an artificial short route for cell-free biosynthesis of the phenethylisoquinoline scaffold.

Plant-originated natural products are important drug sources. However, total biosynthesis of these compounds is often not achievable due to their uncharacterized, lengthy biosynthetic pathways. In nature, phenethylisoquinoline alkaloids (PIAs) such as colchicine are biosynthesized via a common precursor 6,7-dihydroxy-1-(4-hydroxyphenylethyl)-1,2,3,4-tetrahydroisoquinoline (i.e., phenethylisoquinoline scaffold, PIAS). PIAS is naturally synthesized in plants by using two upstream substrates (l-phenylalanine and l-tyrosine) catalyzed by eight enzymes. To shorten this native pathway, here we designed an artificial route to synthesize PIAS with two enzymatic steps from two alternative substrates of 3-(4-hydroxyphenyl) propanol (4-HPP) and dopamine. In the two-step bioconversion, an alcohol dehydrogenase selected from yeast (i.e., ADH7) was able to oxidize its non-native alcohol substrate 4-HPP to form the corresponding aldehyde product, which was then condensed with dopamine by the (S)-norcoclaurine synthase (NCS) to synthesize PIAS. After optimization, the final enzymatic reaction system was successfully scaled up by 200 times from 50 µL to 10 mL, generating 5.4 mM of PIAS. We envision that this study will provide an easy and sustainable approach to produce PIAS and thus lay the foundation for large-scale production of PIAS-derived natural products.

Mouse Pramel1 regulates spermatogonial development by inhibiting retinoic acid signaling during spermatogenesis.

Spermatogenesis begins when cell fate-committed prospermatogonia migrate to the basement membrane and initiate spermatogenesis in response to retinoic acid (RA) in the neonatal testis. The underlying cellular and molecular mechanisms in this process are not fully understood. Here, we report findings on the involvement of a cancer/testis antigen, PRAMEL1, in the initiation and maintenance of spermatogenesis. By analyzing mouse models with either global or conditional Pramel1 inactivation, we found that PRAMEL1 regulates the RA responsiveness of the subtypes of prospermatogonia in the neonatal testis, and affects their homing process during the initiation of spermatogenesis. Pramel1 deficiency led to increased fecundity in juvenile males and decreased fecundity in mature males. In addition, Pramel1 deficiency resulted in a regional Sertoli cell-only phenotype during the first round of spermatogenesis, which was rescued by administration of the RA inhibitor WIN18,446, suggesting that PRAMEL1 functions as an inhibitor of RA signaling in germ cells. Overall, our findings suggest that PRAMEL1 fine-tunes RA signaling, playing a crucial role in the proper establishment of the first and subsequent rounds of spermatogenesis.

Novel Dual-Mode NIR-II/MRI Nanoprobe Targeting PD-L1 Accurately Evaluates the Efficacy of Immunotherapy for Triple-Negative Breast Cancer.

Background: Durable responses to immune-checkpoint blocking therapy (ICT) targeting programmed cell death protein-1/ligand-1 (PD-1/PD-L1) have improved outcomes for patients with triple negative breast cancer (TNBC). Unfortunately, only 19-23% of patients benefit from ICT. Hence, non-invasive strategies evaluating responses to therapy and selecting patients who will benefit from ICT are critical issues for TNBC immunotherapy. Methods: We developed a novel nanoparticle-Atezolizumab (NPs-Ate) consisting of indocyanine green (ICG), gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), human serum albumin (HSA), and Atezolizumab. The efficiency of Gd-DTPA linking was verified using mass spectrometry, and the size of NPs-Ate was characterized using Nano-flow cytometry. The synthesized NPs-Ate were evaluated for fluorescence stability, penetration depth, and target specificity. TNBC cell lines and tumor-bearing mice models were used to identify the feasibility of this dual-modal second near-infrared/magnetic resonance imaging (NIR-II/MRI) system. Additionally, ICT combination with chemotherapy or radiotherapy in TNBC tumor-bearing mice models were used to assess dynamic changes of PD-L1 and predicted therapeutic responses with NPs-Ate. Results: Atezolizumab, a monoclonal antibody, was successfully labeled with ICG and Gd-DTPA to generate NPs-Ate. This demonstrated strong fluorescence signals in our NIR-II imaging system, and relaxivity (γ1) of 9.77 mM-1 s-1. In tumor-bearing mice, the NIR-II imaging signal background ratio (SBR) reached its peak of 11.51 at 36 hours, while the MRI imaging SBR reached its highest as 1.95 after 12 hours of tracer injection. NPs-Ate specifically targets cells and tumors expressing PD-L1, enabling monitoring of PD-L1 status during immunotherapy. Combining therapies led to inhibited tumor growth, prolonged survival, and increased PD-L1 expression, effectively monitored using the non-invasive NPs-Ate imaging system. Conclusion: The NIR-II/MRI NPs-Ate effectively reflected PD-L1 status during immunotherapy. Real-time and non-invasive immunotherapy and response/prognosis monitoring under NIR-II/MRI imaging guidance in TNBC is a promising and innovative technology with potential for extensive clinical applications in the future.

Application of single-cell RNA sequencing in head and neck squamous cell carcinoma.

Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma (HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells' expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancer-associated fibroblasts (CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-to-mesenchymal transition (EMT) model and the mechanism of drug resistance, as well as its clinical value.