[Comparison of the ability of four different kinds of nickel-titanium instruments to prepare simulated resin to simulate curved root canal forming].

PURPOSE: To compare the forming ability of four kinds of nickel-titanium instrument preparation resin for simulated curved root canal. METHODS: A total of 40 single bend resin simulated root canals were randomly divided into 4 groups with 10 in each group. Four kinds of nickel-titanium instruments (ProTaper, HyFlex EDM, WaveOne Gold and Reciproc Blue) were used for root canal preparation, and divided into group A, group B, group C and group D. The preparation time of the four groups was compared, the root canal images before and after preparation were analyzed by computer image analysis software, and the changes of the preparation time, curvature and curvature radius of the four groups were recorded. With the root tip as the center of the circle, the radius of 1-10 mm was selected as concentric circle arcs. The detection points were overlapping root canal intersection points. The resin removal amount and center positioning force of the inner and outer walls of the root canal at different detection points were recorded. Statistical analysis was performed with SPSS 20.0 software package. RESULTS: The root canal preparation time in group A was significant longer than that in group B, C and D(P＜0.05), but there was no significant difference in the curvature and curvature radius of the root canal among the four groups (P＞0.05). The removal amount of resin from the root canal wall in group C was significant lower than that in group A, B and D (P＜0.05) when the distance from the detection point to the apical foramina was 5, 6, 8, 9 and 10 mm, respectively. The removal amount of resin from the outer wall of the root canal in group C was significant lower than that in group A, B and D (P＜0.05) when the distance from the detection point to the apical foramina was 5, 6, 7, 9 and 10 mm, respectively. The root tip offset of group A from the detection point to the apical hole of 1, 2, 3, 4, 6, 7, 8, 9 and 10 mm was significant greater than that of group B, C and D(P＜0.05). CONCLUSIONS: Among the four instruments, ProTaper has the largest apical deviation, HyFlex EDM, WaveOne Gold and Reciproc Blue have better ability of root canal forming.

Targeting PARP14 with lomitapide suppresses drug resistance through the activation of DRP1-induced mitophagy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that remains incurable, primarily due to the high likelihood of relapse or development of resistance to current treatments. To explore and discover new medications capable of overcoming drug resistance in MM, we conducted cell viability inhibition screens of 1504 FDA-approved drugs. Lomitapide, a cholesterol-lowering agent, was found to exhibit effective inhibition on bortezomib-resistant MM cells in vitro and in vivo. Our data also indicated that lomitapide decreases the permeability of the mitochondrial outer membrane and induces mitochondrial dysfunction in MM cells. Next, lomitapide treatment upregulated DRP1 and PINK1 expression levels, coupled with the mitochondrial translocation of Parkin, leading to MM cell mitophagy. Excessive mitophagy caused mitochondrial damage and dysfunction induced by lomitapide. Meanwhile, PARP14 was identified as a direct target of lomitapide by SPR-HPLC-MS, and we showed that DRP1-induced mitophagy was crucial in the anti-MM activity mediated by PARP14. Furthermore, PARP14 is overexpressed in MM patients, implying that it is a novel therapeutic target in MM. Collectively, our results demonstrate that DRP1-mediated mitophagy induced by PARP14 may be the cause for mitochondrial dysfunction and damage in response to lomitapide treatment.

Non-coding RNAs' function in cancer development, diagnosis and therapy.

While previous research on cancer biology has focused on genes that code for proteins, in recent years it has been discovered that non-coding RNAs (ncRNAs)play key regulatory roles in cell biological functions. NcRNAs account for more than 95% of human transcripts and are an important entry point for the study of the mechanism of cancer development. An increasing number of studies have demonstrated that ncRNAs can act as tumor suppressor genes or oncogenes to regulate tumor development at the epigenetic level, transcriptional level, as well as post-transcriptional level. Because of the importance of ncRNAs in cancer, most clinical trials have focused on ncRNAs to explore whether ncRNAs can be used as new biomarkers or therapies. In this review, we focus on recent studies of ncRNAs including microRNAs (miRNAs), long ncRNAs (lncRNAs), circle RNAs (circRNAs), PIWI interacting RNAs (piRNAs), and tRNA in different types of cancer and explore the application of these ncRNAs in the development of cancer and the identification of relevant therapeutic targets and tumor biomarkers. Graphical abstract drawn by Fidraw.

The effect of phytochemicals in N-methyl-N-nitro-N-nitroguanidine promoting the occurrence and development of gastric cancer.

Gastric cancer is a common malignant tumor of the digestive tract, with a low early diagnosis rate. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the main risk factors for gastric cancer. Phytochemicals are healthy active substances derived from vegetables, fruits, nuts, tea, herbal medicines and other plants. Taking phytochemicals is a very promising strategy for the prevention and treatment of gastric cancer. Many studies have proved that phytochemicals have protective effects on MNNG induced gastric cancer via inhibiting cell proliferation, enhancing immunity, suppressing cell invasion and migration, inducing apoptosis and autophagy, blocking angiogenesis, inhibiting Helicobacter pylori infection as well as regulating metabolism and microbiota. The intervention and therapeutic effects of phytochemicals in MNNG induced gastric cancer have attracted more and more attention. In order to better study and explore the role, advantages and challenges of phytochemicals in MNNG induced gastric cancer, we summarized the intervention and therapeutic effects of phytochemicals in MNNG induced gastric cancer. This review may help to further promote the research and clinical application of phytochemicals in MNNG induced gastric cancer, and provide some new insights.

Donor-derived CAR-T therapy improves the survival of relapsed B-ALL after allogeneic transplantation compared with donor lymphocyte infusion.

Chimeric antigen receptor (CAR)-T cell therapy revolutionized treatment for various hematologic malignances. However, limited studies were reported to compare the efficacy and safety of CAR-T and donor lymphocyte infusion (DLI) for patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) after hematopoietic stem cell transplantation (HSCT) comprehensively. We conducted a single-center, retrospective comparative study that consisted of 12 patients who were treated with DLI (control group) and 12 patients treated with donor-derived CD19 CAR-T cells (experimental group, 6 patients also received CD22 or CD123 CAR-T cells sequentially) with 3 overlaps. The event-free survival (EFS) of patients in experimental group was superior to that of the control group: 516 days versus 98 days (p = 0.0415). Compared with 7 of 12 patients treated with DLI suffered grades III-IV acute graft versus host disease (aGVHD), one grade III aGVHD developed in patients treated with CAR-T therapy. No significant difference in the incidence of infection was identified between these two groups. Most patients in the experimental group had only mild cytokine release syndrome and none developed neurotoxicity. The univariate analysis of patients in the experiment group revealed that earlier CAR-T therapy for post-transplantation relapse was associated with better EFS. There was no significant difference in EFS between patients treated with dual-target CAR-T with those with single CD19 CAR-T. In this study, our data supported that donor-derived CAR-T therapy is a safe and potentially effective treatment for relapsed B-ALL after HSCT and may be superior to DLI.

Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

Cyclic-di-AMP signalling in lactic acid bacteria.

Cyclic dimeric adenosine monophosphate (cyclic-di-AMP) is a nucleotide second messenger present in Gram-positive bacteria, Gram-negative bacteria and some Archaea. The intracellular concentration of cyclic-di-AMP is adjusted in response to environmental and cellular cues, primarily through the activities of synthesis and degradation enzymes. It performs its role by binding to protein and riboswitch receptors, many of which contribute to osmoregulation. Imbalances in cyclic-di-AMP can lead to pleiotropic phenotypes, affecting aspects such as growth, biofilm formation, virulence, and resistance to osmotic, acid, and antibiotic stressors. This review focuses on cyclic-di-AMP signalling in lactic acid bacteria (LAB) incorporating recent experimental discoveries and presenting a genomic analysis of signalling components from a variety of LAB, including those found in food, and commensal, probiotic, and pathogenic species. All LAB possess enzymes for the synthesis and degradation of cyclic-di-AMP, but are highly variable with regards to the receptors they possess. Studies in Lactococcus and Streptococcus have revealed a conserved function for cyclic-di-AMP in inhibiting the transport of potassium and glycine betaine, either through direct binding to transporters or to a transcriptional regulator. Structural analysis of several cyclic-di-AMP receptors from LAB has also provided insights into how this nucleotide exerts its influence.

Cyr61 Mediates Angiotensin II-Induced Podocyte Apoptosis via the Upregulation of TXNIP.

Purpose: It is well documented that angiotensin II (Ang II) elevation promotes apoptosis of podocytes in vivo and vitro, but the potential mechanism is still oscular. The current study is aimed at probing into the assignment of cysteine-rich protein 61 (Cyr61) in Ang II-induced podocyte apoptosis. Methods: Podocytes were treated with Ang II (10-6 mol/L) for 48 hours to establish an injury model in vitro. Western blot assays were detected the expression of Cyr61, Cyt-c, Bax, and Bcl-2. Gene microarray was used to analyze the expression of mRNAs after treatment with Ang II. CRISPR/Cas9 technology was used to knock down Cyr61 and overexpress TXNIP gene, respectively. Results: The expression of Cyr61, TXNIP, Cyt-c, and Bax in podocytes treated with Ang II were upregulated, but the expression and apoptotic rates of Bcl-2 in podocytes were inhibited. The level of the above factors was not significantly different after the knockdown of Cyr61 with Ang II in podocytes. In Ang II group, when knocked down Cyr61, the expressed level of TXNIP, Cyt-c, and Bax was diminished after Ang II treatment; interestingly Bcl-2 expression and podocyte apoptotic rate were reduced. Under the stimulation of Ang II, the expression of Cyt-c and Bax were growing, whereas Bcl-2 was reduced, and the apoptotic rates were higher in the TXNIP overexpression group. Cyt-c and Bax were put on, whereas that of Bcl-2 was to be cut down when the Cyr61 was knockdown, and the apoptotic rates were gained in the TXNIP overexpression+Cyr61 knockdown group. Conclusions: The results of the study extrapolate that Cyr61 plays a dominant role in Ang II-induced podocyte apoptosis. Additionally, Cyr61 may mediate the Ang II-induced podocyte apoptosis by promoting the expression of TNXIP.

Influences of compound exercises on jumpingin volleyball / Influências de exercícios compostos sobre o salto no voleibol / Influencia de los ejercicios compuestos en el salto en voleibol

ABSTRACT Introduction: Volleyball requires athletes to have high global sport capacity. Compound exercises require more than one muscle group to complete a given movement. They are ideal for jump development in volleyball because they replicate how the athlete's body moves naturally. However, the attributes relevant to this technique are not fully understood. Objective: Study compound exercise's effects on volleyball players' jumping ability. Methods: The controlled experiment method was used in 30 volunteers equally distributed in two groups, with a duration of 8 weeks. The control group received traditional training. The experimental group received training sessions directed by compound exercises. The sessions were applied twice a week, lasting 80 minutes per session, including 15 minutes of warm-up and 10 minutes of cool-down. The indicators were collected individually before and after the experiment, and the data were analyzed and statistically confronted. Results: The experimental group showed better results on standing vertical jump height, touch height, and blocking height after the compound exercise. Conclusion: The proposed compound exercise can improve players' physical quality, impacting their professional quality, to ensure sporting interest. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O voleibol exige que os atletas tenham alta capacidade esportiva global. Os exercícios compostos requerem mais de um grupo muscular trabalhando em conjunto para completar um determinado movimento, sendo ideal para o desenvolvimento de salto no esporte do voleibol por replicar a maneira como o corpo do atleta move-se naturalmente. Porém, os atributos relevantes para essa técnica não estão totalmente esclarecidos. Objetivo: Estudar os efeitos do exercício composto na capacidade de salto dos jogadores de voleibol. Métodos: Utilizou-se o método de experimento controlado em 30 voluntários igualmente distribuídos em dois grupos, com duração de 8 semanas. O grupo controle recebeu o treinamento tradicional. Treinamentos direcionados foram direcionados por exercícios compostos ao grupo experimental. A sessões foram aplicadas duas vezes por semana, com duração de 80 minutos por sessão, incluindo 15 minutos de aquecimento e 10 minutos resfriamento. Os indicadores forem coletados individualmente antes e depois do experimento, os dados foram analisados e confrontados estatisticamente. Resultados: O grupo experimental apresentou melhores resultados sobre a altura do salto vertical em pé, altura de toque e altura de bloqueio após o exercício composto. Conclusão: O exercício composto proposto pode melhorar a qualidade física dos jogadores, impactando na qualidade profissional, com a premissa de garantir o interesse esportivo. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El voleibol exige que los atletas tengan una alta capacidad deportiva global. Los ejercicios compuestos requieren más de un grupo muscular trabajando en conjunto para completar un movimiento determinado, siendo ideal para el desarrollo del salto en el deporte del voleibol por replicar la forma en que el cuerpo del atleta se mueve naturalmente. Sin embargo, los atributos relevantes para esta técnica no se conocen del todo. Objetivo: Estudiar los efectos del ejercicio compuesto sobre la capacidad de salto de los jugadores de voleibol. Métodos: Se utilizó el método de experimento controlado en 30 voluntarios distribuidos equitativamente en dos grupos, con una duración de 8 semanas. El grupo de control recibió formación tradicional. El grupo experimental recibió sesiones de entrenamiento dirigidas por ejercicios compuestos. Las sesiones se aplicaron dos veces por semana, con una duración de 80 minutos por sesión, incluidos 15 minutos de calentamiento y 10 minutos de enfriamiento. Los indicadores se recogieron individualmente antes y después del experimento, se analizaron los datos y se confrontaron estadísticamente. Resultados: El grupo experimental mostró mejores resultados en la altura de salto vertical de pie, la altura de toque y la altura de bloqueo tras el ejercicio compuesto. Conclusión: El ejercicio compuesto propuesto puede mejorar la calidad física de los jugadores, repercutiendo en la calidad profesional, con la premisa de garantizar el interés deportivo. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Upper limbs physical fitness training in volleyball players / Treinamento de aptidão física de membros superiores em jogadores de voleibol / Entrenamiento de aptitud física de los miembros superiores en jugadores de voleibol

ABSTRACT Introduction: Dedicated fitness training has greatly influenced many qualities required of volleyball players, but specific upper limb training is still poorly documented. Objective: Study the impacts of fitness training on upper limb strength and functional impacts during volleyball players' ball throws. Methods: Twenty volleyball students were randomly divided into experimental and control groups for a six-week experiment. The experimental group mainly performed a training protocol involving ball throws while the control group continued with traditional training methods. The data regarding functional kinematics and fitness performance were collected and statistically compared. Results: In the experimental group, shoulder flexor strength evidenced an increase from 0.41±0.19 J/kg to 1.29±0.19 J/kg; elbow flexor strength elevated from 0.38±0.23 J/kg to 1.61±0.02 J/kg. On the specific functional performance, the peak score increased from 4.84±1.44 to 7.47±1.43; The overall score increased from 9.05±1.70 to 13.31±1.72. It was noted that the rate of increase of each index was more significant than that of the control group. Conclusion: Dedicated fitness training can improve the upper limb strength and hitting effect of volleyball players, and its combination with special strength training is recommended to improve the overall skills of athletes. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O treinamento dedicado de aptidão física tem mostrado grande influência sobre muitas qualidades requisitadas aos jogadores de voleibol, porém o treinamento específico em membros superiores ainda é pouco documentado. Objetivo: Estudar os impactos do treinamento de aptidão física sobre a força dos membros superiores e os impactos funcionais durante os arremessos de bola dos jogadores de voleibol. Métodos: Vinte estudantes de voleibol foram divididos aleatoriamente em grupo experimental e controle para uma experiência de 6 semanas. O grupo experimental realizou principalmente um protocolo de treinamento envolvendo arremessos de bola enquanto o grupo de controle prosseguiu com os métodos tradicionais de treinamento. Dados referentes a cinemática funcional e desempenho de aptidão física foram coletados e comparados estatisticamente. Resultados: No grupo experimental, a força do flexor do ombro evidenciou um aumento de 0,41±0,19 J/kg para 1,29±0,19 J/kg; a força do flexor do cotovelo elevou-se de 0,38±0,23 J/kg para 1,61±0,02 J/kg. Sobre o desempenho funcional específico, a pontuação do pico aumentou de 4,84±1,44 para 7,47±1,43; A pontuação geral aumentou de 9,05±1,70 para 13,31±1,72. Notou-se que a taxa de aumento de cada índice foi mais significativa do que a do grupo de controle. Conclusão: O treinamento dedicado de aptidão física pode melhorar a força dos membros superiores e o efeito de acertos dos jogadores de vôlei, sendo recomendada a sua combinação com o treinamento especial de força para melhorar as habilidades gerais dos atletas. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: El entrenamiento físico específico ha demostrado una gran influencia en muchas cualidades exigidas a los jugadores de voleibol, pero el entrenamiento específico de extremidades superiores está aún poco documentado. Objetivo: Estudiar las repercusiones del entrenamiento físico en la fuerza de los miembros superiores y los impactos funcionales durante los lanzamientos de balón de los jugadores de voleibol. Métodos: Veinte estudiantes de voleibol fueron divididos aleatoriamente en grupo experimental y de control para un experimento de 6 semanas. El grupo experimental realizó principalmente un protocolo de entrenamiento que incluía lanzamientos de balón, mientras que el grupo de control continuó con los métodos de entrenamiento tradicionales. Se recogieron y compararon estadísticamente los datos relativos a la cinemática funcional y el rendimiento físico. Resultados: En el grupo experimental, la fuerza flexora del hombro evidenció un aumento de 0,41±0,19 J/kg a 1,29±0,19 J/kg; la fuerza flexora del codo se elevó de 0,38±0,23 J/kg a 1,61±0,02 J/kg. Respecto al rendimiento funcional específico, la puntuación máxima aumentó de 4,84±1,44 a 7,47±1,43; la puntuación global aumentó de 9,05±1,70 a 13,31±1,72. Se observó que el índice de aumento de cada índice fue más significativo que el del grupo de control. Conclusión: El entrenamiento físico dedicado puede mejorar la fuerza de las extremidades superiores y el efecto de golpeo de los jugadores de voleibol, y se recomienda su combinación con un entrenamiento especial de fuerza para mejorar las habilidades generales de los atletas. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Gastric cancer stem cell-derived exosomes promoted tobacco smoke-triggered development of gastric cancer by inducing the expression of circ670.

As one of the most common malignant cancers in the world, gastric cancer is caused by mang factors among which tobacco smoke is an important risk factor. Gastric cancer stem cells (GCSCs) and the derived exosomes play a key role in the occurrence and development of gastric cancer, and exosomal circRNA is considered as a new regulatory factor in the development of gastric cancer. However, it is unclear whether tobacco smoke can affect exosomes and their transport circRNAs to promote the development of gastric cancer. Herein, we provided a new insight into tobacco smoke promoting the progression of gastric cancer. In the present study, we demonstrated that tobacco smoke-induced exosomes promoted the spheroidizing ability, stemness genes expression, and epithelial-mesenchymal transition (EMT) process of GCSCs. We further found that hsa-circRNA-000670 (circ670) was up-regulated in tissues of gastric cancer patients with smoking history, tobacco smoke-induced GCSCs, and their exosomes. Functional assays have shown that circ670 knockdown inhibited the stemness and EMT process of GCSCs, whereas circ670 overexpression appeared to have an opposite effect. Our findings indicated that exosomal circ670 promotes the development of tobacco smoke-induced gastric cancer, which may provide insight into the mechanism of tobacco smoke promoting the progression of gastric cancer.

Characterization of the Biosynthetic Gene Cluster and Shunt Products Yields Insights into the Biosynthesis of Balmoralmycin.

Angucyclines are a family of structurally diverse, aromatic polyketides with some members that exhibit potent bioactivity. Angucyclines have also attracted considerable attention due to the intriguing biosynthetic origins that underlie their structural complexity and diversity. Balmoralmycin (compound 1) represents a unique group of angucyclines that contain an angular benz[α]anthracene tetracyclic system, a characteristic C-glycosidic bond-linked deoxy-sugar (d-olivose), and an unsaturated fatty acid chain. In this study, we identified a Streptomyces strain that produces balmoralmycin and seven biosynthetically related coproducts (compounds 2-8). Four of the coproducts (compounds 5-8) are novel compounds that feature a highly oxygenated or fragmented lactone ring, and three of them (compounds 3-5) exhibited cytotoxicity against the human pancreatic cancer cell line MIA PaCa-2 with IC50 values ranging from 0.9 to 1.2 µg/mL. Genome sequencing and CRISPR/dCas9-assisted gene knockdown led to the identification of the ~43 kb balmoralmycin biosynthetic gene cluster (bal BGC). The bal BGC encodes a type II polyketide synthase (PKS) system for assembling the angucycline aglycone, six enzymes for generating the deoxysugar d-olivose, and a hybrid type II/III PKS system for synthesizing the 2,4-decadienoic acid chain. Based on the genetic and chemical information, we propose a mechanism for the biosynthesis of balmoralmycin and the shunt products. The chemical and genetic studies yielded insights into the biosynthetic origin of the structural diversity of angucyclines. IMPORTANCE Angucyclines are structurally diverse aromatic polyketides that have attracted considerable attention due to their potent bioactivity and intriguing biosynthetic origin. Balmoralmycin is a representative of a small family of angucyclines with unique structural features and an unknown biosynthetic origin. We report a newly isolated Streptomyces strain that produces balmoralmycin in a high fermentation titer as well as several structurally related shunt products. Based on the chemical and genetic information, a biosynthetic pathway that involves a type II polyketide synthase (PKS) system, cyclases/aromatases, oxidoreductases, and other ancillary enzymes was established. The elucidation of the balmoralmycin pathway enriches our understanding of how structural diversity is generated in angucyclines and opens the door for the production of balmoralmycin derivatives via pathway engineering.

Role of ferroptosis and ferroptosis-related non-coding RNAs in the occurrence and development of gastric cancer.

Gastric cancer (GC) is a malignant cancer of the digestive tract and is a life-threatening disease worldwide. Ferroptosis is a newly discovered form of regulated cell death, which involves the accumulation of iron-dependent lipid peroxides. It has been found that ferroptosis plays an important regulatory role in the occurrence, development, drug resistance, and prognosis of GC. Non-coding RNAs (ncRNAs) play a critical role in the occurrence and progression of a variety of diseases including GC. In recent years, the role of ferroptosis and ferroptosis-related ncRNAs (miRNA, lncRNA, and circRNA) in the occurrence, development, drug resistance, and prognosis of GC has attracted more and more attention. Herein, we briefly summarize the roles and functions of ferroptosis and ferroptosis-related ncRNAs in GC tumorigenesis, development, and prognosis. We also prospected the future research direction and challenges of ferroptosis and ferroptosis-related ncRNAs in GC.

FAM96A and FAM96B function as new tumor suppressor genes in breast cancer through regulation of the Wnt/ß-catenin signaling pathway.

AIMS: Family with sequence similarity 96 member A and B (FAM96A and FAM96B) are two highly conserved homologous proteins belonging to MIP18 family. Some studies have shown that FAM96A and FAM96B are significantly down-regulated in human gastrointestinal stromal tumors, colon cancer, and liver cancer. However, the molecular mechanisms of FAM96A/B in breast cancer are unknown. This work aims to explore the roles of FAM96A/B in breast cancer progression. MAIN METHODS: Specific siRNAs were used to down-regulate FAM96A/B expression, and recombinant plasmids were used to up-regulate FAM96A/B expression in breast cancer cells. Cell proliferation was measured using MTT and colony formation. Cell cycle and apoptosis were detected by flow cytometry. Cell migration and invasion were examined by wound healing and transwell assays. The relationships among FAM96A/B, EMT and Wnt/ß-catenin pathway were determined by analyzing expression changes of classical markers. KEY FINDINGS: We found that FAM96A/B expression was down-regulated in breast cancer. FAM96A/B overexpression suppressed breast cancer cell proliferation, invasion and migration, induced cell apoptosis and caused cell cycle arrest. Conversely, FAM96A/B knockdown exhibited the opposite effects. Moreover, our data demonstrated that FAM96A/B overexpression suppressed EMT and Wnt/ß-catenin pathway, while FAM96A/B knockdown showed the promoting effects on EMT and Wnt/ß-catenin pathway. Furthermore, a Wnt pathway inhibitor, XAV-939 reversed the promoting effects of FAM96A/B knockdown on breast cancer progression. SIGNIFICANCE: Our findings suggest that FAM96A/B may function as new tumor suppressor genes and inhibit breast cancer progression via modulating Wnt/ß-catenin pathway, which can provide the potential markers for breast cancer diagnosis and therapy.

RALY regulate the proliferation and expression of immune/inflammatory response genes via alternative splicing of FOS.

RALY is a multifunctional RNA-binding protein involved in cancer metastasis, prognosis, and chemotherapy resistance in various cancers. However, the molecular mechanism of which is still unclear. We have established RALY overexpression cell lines and studied the effect of RALY on proliferation and apoptosis in HeLa cells. Then we used RNA-seq to analyze the transcriptomes data. Lastly, RT-qPCR experiments had performed to confirm the RNA-seq results. We found that the overexpression of RALY in HeLa cells inhibited proliferation. Moreover, the overexpression of RALY changed the gene expression profile, and the significant upregulation of genes involved immune/inflammatory response related biological process by NOD-like receptor signaling pathway cytokine-cytokine receptor interaction. The significant downregulation genes involved innate immune response by the Primary immunodeficiency pathway. Notably, IFIT1, IFIT2, IFTI3, IFI44, HERC4, and OASL expression had inhibited by the overexpression of RALY. Furthermore, RALY negatively regulates the expression of transcription factors FOS and FOSB. Notably, we found that 645 alternative splicing events had regulated by overexpression of RALY, which is highly enriched in transcription regulation, RNA splicing, and cell proliferation biological process by the metabolic pathway. We show that RALY regulates the expression of immune/inflammatory response-related genes via alternative splicing of FOS in HeLa cells. The novel role of RALY in regulating immune/inflammatory gene expression may explain its function in regulating chemotherapy resistance and provides novel insights into further exploring the molecular mechanism of RALY in regulating cancer immunity and chemo/immune therapies.

Circular RNA and Its Roles in the Occurrence, Development, Diagnosis of Cancer.

Circular RNAs (circRNAs) are non-coding single-stranded covalently closed circular RNA, mainly produced by reverse splicing of exons of precursor mRNAs (pre-mRNAs). The characteristics of high abundance, strong specificity, and good stability of circRNAs have been discovered. A large number of studies have reported its various functions and mechanisms in biological events, such as the occurrence and development of cancer. In this review, we focus on the classification, characterization, biogenesis, functions of circRNAs, and the latest advances in cancer research. The development of circRNAs as biomarkers in cancer diagnosis and treatment also provides new ideas for studying circRNAs research.

Current state of CAR-T therapy for T-cell malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy has been approved for relapsed/refractory B-cell lymphomas and greatly improves disease outcomes. The impressive success has inspired the application of this approach to other types of tumors. The relapsed/refractory T-cell malignancies are characteristic of high heterogeneity and poor prognoses. The efficacy of current treatments for this group of diseases is limited. CAR-T therapy is a promising solution to ameliorate the current therapeutic situation. One of the major challenges is that normal T-cells typically share mutual antigens with malignant cells, which causes fratricide and serious T-cell aplasia. Moreover, T-cells collected for CAR transduction could be contaminated by malignant T-cells. The selection of suitable target antigens is of vital importance to mitigate fratricide and T-cell aplasia. Using nanobody-derived or naturally selected CAR-T is the latest method to overcome fratricide. Allogeneic CAR-T products and CAR-NK-cells are expected to avoid tumor contamination. Herein, we review the advances in promising target antigens, the current results of CAR-T therapy clinical trials in T-cell malignancies, the obstacles of CAR-T therapy in T-cell malignancies, and the solutions to these issues.

Fungal Endophytes: A Promising Frontier for Discovery of Novel Bioactive Compounds.

For years, fungi have served as repositories of bioactive secondary metabolites that form the backbone of many existing drugs. With the global rise in infections associated with antimicrobial resistance, in addition to the growing burden of non-communicable disease, such as cancer, diabetes and cardiovascular ailments, the demand for new drugs that can provide an improved therapeutic outcome has become the utmost priority. The exploration of microbes from understudied and specialized niches is one of the promising ways of discovering promising lead molecules for drug discovery. In recent years, a special class of plant-associated fungi, namely, fungal endophytes, have emerged as an important source of bioactive compounds with unique chemistry and interesting biological activities. The present review focuses on endophytic fungi and their classification, rationale for selection and prioritization of host plants for fungal isolation and examples of strategies that have been adopted to induce the activation of cryptic biosynthetic gene clusters to enhance the biosynthetic potential of fungal endophytes.

Pathway Retrofitting Yields Insights into the Biosynthesis of Anthraquinone-Fused Enediynes.

Anthraquinone-fused enediynes (AQEs) are renowned for their distinctive molecular architecture, reactive enediyne warhead, and potent anticancer activity. Although the first members of AQEs, i.e., dynemicins, were discovered three decades ago, how their nitrogen-containing carbon skeleton is synthesized by microbial producers remains largely a mystery. In this study, we showed that the recently discovered sungeidine pathway is a "degenerative" AQE pathway that contains upstream enzymes for AQE biosynthesis. Retrofitting the sungeidine pathway with genes from the dynemicin pathway not only restored the biosynthesis of the AQE skeleton but also produced a series of novel compounds likely as the cycloaromatized derivatives of chemically unstable biosynthetic intermediates. The results suggest a cascade of highly surprising biosynthetic steps leading to the formation of the anthraquinone moiety, the hallmark C8-C9 linkage via alkyl-aryl cross-coupling, and the characteristic epoxide functionality. The findings provide unprecedented insights into the biosynthesis of AQEs and pave the way for examining these intriguing biosynthetic enzymes.

Transforming growth factor-ß1-induced podocyte injury is associated with increased microRNA-155 expression, enhanced inflammatory responses and MAPK pathway activation.

MicroRNA-155 (miR-155) is associated with various diseases. However, the potential role of miR-155 in early glomerular disease (EGD) remains elusive. In the present study, the clinical significance of urinary miR-155 expression was explored in patients with EGD using receiver operating characteristic curve analysis. Conditionally immortalized mouse podocytes were cultured in vitro and treated with transforming growth factor-ß1 (TGF-ß1) at different concentrations and durations. The gene expression levels of mRNAs and miR-155 were detected using reverse transcription-quantitative PCR. Synaptopodin, CD2-associated protein (CD2AP), p38, and extracellular signal-regulated kinase (Erk) 1/2 expressions were detected using western blotting. Cell supernatants were collected for assaying tumor necrosis factor (TNF)-α and interleukin (IL)-6 concentrations using enzyme-linked immunosorbent assay. The Pearson correlation analysis was used to analyze the correlation between miR-155 levels and TNF-α or IL-6. It was found that miR-155 levels in urine have high sensitivity and specificity in the diagnosis of EGD. Time- and dose-dependent TGF-ß1 treatments downregulated synaptopodin and CD2AP expression levels, and activated the p38 and Erk 1/2 pathway. However, these effects were attenuated by p38 and Erk 1/2 phosphorylation inhibitors. Additionally, TNF-α and IL-6 secretions were elevated, and their concentrations were positively correlated with the expression of miR-155 during podocyte injury. Thus, the present study indicated that miR-155 is a potential biomarker for the diagnosis of EGD, and its expression is associated with the release of pro-inflammatory cytokines and activation of mitogen-activated protein kinase (MAPK) pathway in TGF-ß1-induced podocyte injury. The present study suggests that the TGF-ß1/miR-155/MAPK axis is a novel target in the mechanism of EGD.