Recent contributions of pyridazine as a privileged scaffold of anticancer agents in medicinal chemistry: An updated review.

Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.

Long Non-coding RNA LINC00342 Promotes the Proliferation, Invasion, and Migration of Primary Hepatocellular Carcinoma Cells by Regulating the Expression of miRNA-19a-3p, miRNA-545-5p, and miRNA-203a-3p.

This study aimed to investigate the role of the long non-coding RNA (lncRNA) LINC00342-207 (LINC00342) in the development and progression of primary hepatocellular carcinoma (HCC). Forty-two surgically resected HCC tissues and corresponding paracancerous tissues were collected from October 2019 to December 2020 and examined for lncRNA LINC00342, microRNA (miR)-19a-3p, miR-545-5p, miR-203a-3p, cell cycle protein D1 (CyclinD1/CCND1), murine double minute 2 (MDM2), and fibroblast growth factor 2 (FGF2) expression. The disease-free survival and overall survival of patients with HCC were followed up. HCC cell lines and the normal hepatocyte cell line HL-7702 were cultured and the expression level of LINC00342 was measured. HepG2 cells were transfected with LINC00342 siRNA, LINC00342 overexpression plasmid, miR-19a-3p mimics and their corresponding suppressors, miR-545-5p mimics and their corresponding suppressors, and miR-203a-3p mimics and their corresponding suppressors. The proliferation, apoptosis, migration, and invasion of HepG2 cells were detected. Stably transfected HepG2 cells were inoculated into the left axilla of male BALB/c nude mice, and the volume and quality of transplanted tumors as well as the expression levels of LINC00342, miR-19a-3p, miR-545-5p, miR-203a-3p, CCND1, MDM2, and FGF2 were examined. LINC00342 played an oncogenic role in HCC and exhibited inhibitory effects on proliferation, migration, and invasion, and promoted the apoptosis of HepG2 cells. Moreover, it inhibited the growth of transplanted tumors in vivo in mice. Mechanistically, the oncogenic effect of LINC00342 was associated with the targeted regulation of the miR-19a-3p/CCND1, miR-545-5p/MDM2, and miR-203a-3p/FGF2 axes.

Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.

The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 µg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.

1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.

Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.

Aquapteridospora jiangxiensis, a new aquatic hyphomycetous fungus from a freshwater habitat in China.

During an investigation of freshwater fungi in Jiangxi province, China, a new hyphomycetous fungus, Aquapteridospora jiangxiensis, was collected and isolated. Aquapteridospora jiangxiensis is characterized by its unbranched and guttulate conidiophores with multi-septa swollen at the base, polyblastic conidiogenous cells with sympodial proliferations, and denticles, and guttulate conidia with a sheath. A photo plate of the macro- and micro-morphology and a muti-loci (ITS, LSU, SSU, TEF1 and RPB2) phylogenetic tree are provided. A key to the species of Aquapteridospora is also presented in this paper.

Development and validation of a computed tomography-based immune ecosystem diversity index as an imaging biomarker in non-small cell lung cancer.

OBJECTIVES: To date, there are no data on the noninvasive surrogate of intratumoural immune status that could be prognostic of survival outcomes in non-small cell lung cancer (NSCLC). We aimed to develop and validate the immune ecosystem diversity index (iEDI), an imaging biomarker, to indicate the intratumoural immune status in NSCLC. We further investigated the clinical relevance of the biomarker for survival prediction. METHODS: In this retrospective study, two independent NSCLC cohorts (Resec1, n = 149; Resec2, n = 97) were included to develop and validate the iEDI to classify the intratumoural immune status. Paraffin-embedded resected specimens in Resec1 and Resec2 were stained by immunohistochemistry, and the density percentiles of CD3+, CD4+, and CD8+ T cells to all cells were quantified to estimate intratumoural immune status. Then, EDI features were extracted using preoperative computed tomography to develop an imaging biomarker, called iEDI, to determine the immune status. The prognostic value of iEDI was investigated on NSCLC patients receiving surgical resection (Resec1; Resec2; internal cohort Resec3, n = 419; external cohort Resec4, n = 96; and TCIA cohort Resec5, n = 55). RESULTS: iEDI successfully classified immune status in Resec1 (AUC 0.771, 95% confidence interval [CI] 0.759-0.783; and 0.770 through internal validation) and Resec2 (0.669, 0.647-0.691). Patients with higher iEDI-score had longer overall survival (OS) in Resec3 (unadjusted hazard ratio 0.335, 95%CI 0.206-0.546, p < 0.001), Resec4 (0.199, 0.040-1.000, p < 0.001), and TCIA (0.303, 0.098-0.944, p = 0.001). CONCLUSIONS: iEDI is a non-invasive surrogate of intratumoural immune status and prognostic of OS for NSCLC patients receiving surgical resection. KEY POINTS: • Decoding tumour immune microenvironment enables advanced biomarkers identification. • Immune ecosystem diversity index characterises intratumoural immune status noninvasively. • Immune ecosystem diversity index is prognostic for NSCLC patients.

Capturing the interactome of newly transcribed RNA.

We combine the labeling of newly transcribed RNAs with 5-ethynyluridine with the characterization of bound proteins. This approach, named capture of the newly transcribed RNA interactome using click chemistry (RICK), systematically captures proteins bound to a wide range of RNAs, including nascent RNAs and traditionally neglected nonpolyadenylated RNAs. RICK has identified mitotic regulators amongst other novel RNA-binding proteins with preferential affinity for nonpolyadenylated RNAs, revealed a link between metabolic enzymes/factors and nascent RNAs, and expanded the known RNA-bound proteome of mouse embryonic stem cells. RICK will facilitate an in-depth interrogation of the total RNA-bound proteome in different cells and systems.

Caries and Restoration Detection Using Bitewing Film Based on Transfer Learning with CNNs.

Caries is a dental disease caused by bacterial infection. If the cause of the caries is detected early, the treatment will be relatively easy, which in turn prevents caries from spreading. The current common procedure of dentists is to first perform radiographic examination on the patient and mark the lesions manually. However, the work of judging lesions and markings requires professional experience and is very time-consuming and repetitive. Taking advantage of the rapid development of artificial intelligence imaging research and technical methods will help dentists make accurate markings and improve medical treatments. It can also shorten the judgment time of professionals. In addition to the use of Gaussian high-pass filter and Otsu's threshold image enhancement technology, this research solves the problem that the original cutting technology cannot extract certain single teeth, and it proposes a caries and lesions area analysis model based on convolutional neural networks (CNN), which can identify caries and restorations from the bitewing images. Moreover, it provides dentists with more accurate objective judgment data to achieve the purpose of automatic diagnosis and treatment planning as a technology for assisting precision medicine. A standardized database established following a defined set of steps is also proposed in this study. There are three main steps to generate the image of a single tooth from a bitewing image, which can increase the accuracy of the analysis model. The steps include (1) preprocessing of the dental image to obtain a high-quality binarization, (2) a dental image cropping procedure to obtain individually separated tooth samples, and (3) a dental image masking step which masks the fine broken teeth from the sample and enhances the quality of the training. Among the current four common neural networks, namely, AlexNet, GoogleNet, Vgg19, and ResNet50, experimental results show that the proposed AlexNet model in this study for restoration and caries judgments has an accuracy as high as 95.56% and 90.30%, respectively. These are promising results that lead to the possibility of developing an automatic judgment method of bitewing film.

Detection of Dental Apical Lesions Using CNNs on Periapical Radiograph.

Apical lesions, the general term for chronic infectious diseases, are very common dental diseases in modern life, and are caused by various factors. The current prevailing endodontic treatment makes use of X-ray photography taken from patients where the lesion area is marked manually, which is therefore time consuming. Additionally, for some images the significant details might not be recognizable due to the different shooting angles or doses. To make the diagnosis process shorter and efficient, repetitive tasks should be performed automatically to allow the dentists to focus more on the technical and medical diagnosis, such as treatment, tooth cleaning, or medical communication. To realize the automatic diagnosis, this article proposes and establishes a lesion area analysis model based on convolutional neural networks (CNN). For establishing a standardized database for clinical application, the Institutional Review Board (IRB) with application number 202002030B0 has been approved with the database established by dentists who provided the practical clinical data. In this study, the image data is preprocessed by a Gaussian high-pass filter. Then, an iterative thresholding is applied to slice the X-ray image into several individual tooth sample images. The collection of individual tooth images that comprises the image database are used as input into the CNN migration learning model for training. Seventy percent (70%) of the image database is used for training and validating the model while the remaining 30% is used for testing and estimating the accuracy of the model. The practical diagnosis accuracy of the proposed CNN model is 92.5%. The proposed model successfully facilitated the automatic diagnosis of the apical lesion.

[Short-chain fatty acid butyrate acid attenuates atherosclerotic plaque formation in apolipoprotein E-knockout mice and the underlying mechanism].

This study was designed to evaluate the role of short-chain fatty acid butyrate acid on intestinal morphology and function, and atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE-/-) mice. ApoE-/- mice on high-fat, high-cholesterol diet were treated with butyrate acid (200 mmol/L) or NaCl (control) in the drinking water for 12 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time PCR analysis and ELISA were used to measure the expression levels of proinflammatory cytokines. Butyrate acid significantly attenuated high-fat, high-cholesterol diet-induced atherosclerotic plaque formation in ApoE-/- mice. Butyrate acid prevented high-fat, high-cholesterol diet-induced inflammation in both the aorta and the circulation, as evidenced by reduced expression of proinflammatory cytokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia lipopolysaccharide (LPS). Butyrate acid induced intestinal expression of the tight junction proteins (Occludin and zona occuldens protein-1), thereby preventing the gut permeability. Butyrate acid dose-dependently upregulated the expression of the tight junction proteins in Caco-2 cells in GPR41-dependent manner. In conclusion, butyrate acid attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.

[Expression, Purification and Bioinformatics Analysis of ß-hexosaminidase of Dermatophagoides farinae].

The DNA fragment encoding ß-hexosaminidase was synthesized, and cloned into pET-28a vector. The constructed plasmid pMD18-T-ß-hexosaminidase was transformed into E. coli Top 10 and followed by expression of the protein induced by IPTG. SDS-PAGE result showed that the relative molecular mass of the recombinant protein was about M, 55 000. The full length of ß-hexosaminidase gene was 1 410 bp. Bioinformatics analysis revealed that ß-hexosaminidase was composed with 469 amino acid residues with a calculated molecular weight of Mr 55,000, and its secondary structure was composed of strand (14.71%), helix (30.70%), and loop (54.58%). ß-hexosaminidase was a hydrophilic protein without signal peptide, and located in the extracellular space.

Down-regulation of testes-specific protease 50 induces apoptosis in human laryngocarcinoma HEp2 cells in a NF-κB-mediated pathway.

Testes-specific protease 50 is a newly reported threonine enzyme. It has similar amino acid sequences and enzymatic structures to some other serine proteases. It is proposed as a laryngocarcinoma-related gene in human beings. The physiological mechanism by which TSP50 exerts its promoting effects in laryngocarcinoma is not yet fully understood. The study investigated the function of TSP50 by suppressing its expression in the HEp2 cell line using a TSP50-specific short hairpin RNA (shRNA). Western bloting and real-time-PCR were used to detect the levels of TSP50. By using MTT, Wound healing, flow cytometric and tumorigenesis assays, the study tested the TSP50 role in human laryngocarcinoma cell growth and apoptosis. The results demonstrated that TSP50 knockdown could inhibit HEp2 cell proliferation and induce apoptosis in vitro in a NF-κB-mediated pathway. The tumorigenicity of TSP50 shRNA-expressing cells were decreased after inoculating into nude mice. The present results provide a new understanding of the TSP50 gene in the progression of laryngocarcinoma and put up a novel therapeutic target for treating this cancer.

Special electromyographic features in a child with paramyotonia congenita: A case report and review of literature.

BACKGROUND: Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on electromyography (EMG), a diagnostic technique. The child's needle EMG unveiled trains of myotonic discharges with notably giant amplitudes, alongside irregular wave trains of myotonic discharges. This distinctive observation had not surfaced in earlier studies. CASE SUMMARY: We report the case of a 3-year-old female child with PMC, who exhibited laryngeal stridor, muffled speech, myotonia from birth. Cold, exposure to cool water, crying, and physical activity exacerbated the myotonia, which was relieved in warmth, yet never normalized. Percussion myotonia was observable in bilateral biceps. Myotonia symptoms remained unchanged after potassium-rich food consumption like bananas. Hyperkalemic periodic paralysis was excluded. Cranial magnetic resonance imaging yielded normal results. Blood potassium remained within normal range, while creatine kinase showed slight elevation. Exome-wide genetic testing pinpointed a heterozygous mutation on chromosome SCN4A: c.3917G>A (p.G1306E). After a six-month mexiletine regimen, symptoms alleviated. CONCLUSION: In this case revealed the two types of myotonic discharges, and had not been documented in other studies. We underscore two distinctive features: Giant-amplitude potentials and irregular waves.

Histone deacetylase 6 as a novel promising target to treat cardiovascular disease.

Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.

APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Molecular footprints of domestication and improvement in soybean revealed by whole genome re-sequencing.

BACKGROUND: Artificial selection played an important role in the origin of modern Glycine max cultivars from the wild soybean Glycine soja. To elucidate the consequences of artificial selection accompanying the domestication and modern improvement of soybean, 25 new and 30 published whole-genome re-sequencing accessions, which represent wild, domesticated landrace, and Chinese elite soybean populations were analyzed. RESULTS: A total of 5,102,244 single nucleotide polymorphisms (SNPs) and 707,969 insertion/deletions were identified. Among the SNPs detected, 25.5% were not described previously. We found that artificial selection during domestication led to more pronounced reduction in the genetic diversity of soybean than the switch from landraces to elite cultivars. Only a small proportion (2.99%) of the whole genomic regions appear to be affected by artificial selection for preferred agricultural traits. The selection regions were not distributed randomly or uniformly throughout the genome. Instead, clusters of selection hotspots in certain genomic regions were observed. Moreover, a set of candidate genes (4.38% of the total annotated genes) significantly affected by selection underlying soybean domestication and genetic improvement were identified. CONCLUSIONS: Given the uniqueness of the soybean germplasm sequenced, this study drew a clear picture of human-mediated evolution of the soybean genomes. The genomic resources and information provided by this study would also facilitate the discovery of genes/loci underlying agronomically important traits.

Potential of bacteriophage ΦAB2 as an environmental biocontrol agent for the control of multidrug-resistant Acinetobacter baumannii.

BACKGROUND: Multidrug-resistant Acinetobacter baumannii (MDRAB) is associated with nosocomial infections worldwide. To date, the use of a phage to prevent infections caused by MDRAB has not been demonstrated. RESULTS: The MDRAB-specific phage ϕAB2 was stable at 4°C and pH 7 in 0.5% chloroform solution, and showed a slight decrease in plaque-forming units (PFU)/ml of 0.3-0.9 log after 330 days of storage. The addition of ϕAB2 at a concentration of at least 105 PFU/ml to an A. baumannii M3237 suspension killed >99.9% of A. baumannii M3237 after 5 min, regardless of A. baumannii M3237 concentration (104, 105, or 106 colony-forming units (CFU)/ml). The addition of ϕAB2 at a concentration of 108 PFU/slide (>107 PFU/cm²) to glass slides containing A. baumannii M3237 at 104, 105, or 106 CFU/slide, significantly reduced bacterial numbers by 93%, 97%, and 99%, respectively. Thus, this concentration is recommended for decontamination of glass surfaces. Moreover, infusion of ϕAB2 into 10% glycerol exhibited strong anti-MDRAB activity (99.9% reduction), even after 90 days of storage. Treatment of a 10% paraffin oil-based lotion with ϕAB2 significantly reduced (99%) A. baumannii M3237 after 1 day of storage. However, ϕAB2 had no activity in the lotion after 1 month of storage. CONCLUSIONS: Phages may be useful for reducing MDRAB contamination in liquid suspensions or on hard surfaces. Phages may also be inoculated into a solution to produce an antiseptic hand wash. However, the phage concentration and incubation time (the duration of phage contact with bacteria) should be carefully considered to reduce the risk of MDRAB contamination.

[Effects of Platelet-Rich Plasma on Macrophage Phenotype and Its Influencing Factors].

OBJECTIVE: To evaluate the effects of platelet-rich plasma (PRP) supernatants with different activation methods and storage time on human monocyte-derived macrophages phenotype and explore the possible mechanism. METHODS: Human monocyte-derived macrophages were cultured in vitro with PRP or activated PRP supernatants activated with different activators. The expression of marker molecules on the surface of macrophages was detected by flow cytometry, and the concentration of growth factors in PRP supernatants was detected by ELISA. RESULTS: After 24 h of coculture, the expression level of CD86 in macrophages stimulated by PRP supernatant (thrombin and Cacl2 activated) was significantly higher than that by PRP group (P<0.05), and the expression of CD163 in macrophages was increased by Cacl2 activated PRP supernatant. Compared with different activator groups, the expression of CD163 in macrophages of Cacl2 activated group was significantly higher than that of thrombin and ADP groups (P<0.05). ELISA results showed that the concentrations of FGF (P<0.001) and EGF (P<0.05) in the supernatant of PRP stored at -80 ℃ for more than 20 months and 10-20 months were significantly higher than those in the group stored at less than 10 months after Cacl2 activation, and the expressions of CD86 (P<0.01), CD163 (P<0.001) and CD206 (P<0.001) in macrophages cocultured with the supernatant of the two groups were significantly increased. CONCLUSION: PRP activated by different activators has different effects on the phenotype of macrophages. Meanwhile, the storage time will also affect the growth factor concentration and effect of PRP.

Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer.

Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.

Deep Learning for Dental Diagnosis: A Novel Approach to Furcation Involvement Detection on Periapical Radiographs.

Furcation defects pose a significant challenge in the diagnosis and treatment planning of periodontal diseases. The accurate detection of furcation involvements (FI) on periapical radiographs (PAs) is crucial for the success of periodontal therapy. This research proposes a deep learning-based approach to furcation defect detection using convolutional neural networks (CNN) with an accuracy rate of 95%. This research has undergone a rigorous review by the Institutional Review Board (IRB) and has received accreditation under number 202002030B0C505. A dataset of 300 periapical radiographs of teeth with and without FI were collected and preprocessed to enhance the quality of the images. The efficient and innovative image masking technique used in this research better enhances the contrast between FI symptoms and other areas. Moreover, this technology highlights the region of interest (ROI) for the subsequent CNN models training with a combination of transfer learning and fine-tuning techniques. The proposed segmentation algorithm demonstrates exceptional performance with an overall accuracy up to 94.97%, surpassing other conventional methods. Moreover, in comparison with existing CNN technology for identifying dental problems, this research proposes an improved adaptive threshold preprocessing technique that produces clearer distinctions between teeth and interdental molars. The proposed model achieves impressive results in detecting FI with identification rates ranging from 92.96% to a remarkable 94.97%. These findings suggest that our deep learning approach holds significant potential for improving the accuracy and efficiency of dental diagnosis. Such AI-assisted dental diagnosis has the potential to improve periodontal diagnosis, treatment planning, and patient outcomes. This research demonstrates the feasibility and effectiveness of using deep learning algorithms for furcation defect detection on periapical radiographs and highlights the potential for AI-assisted dental diagnosis. With the improvement of dental abnormality detection, earlier intervention could be enabled and could ultimately lead to improved patient outcomes.