Effect of different treatment modalities on the prognosis of stage IV epithelial ovarian cancer: analysis of the SEER database.

BACKGROUND: The prognosis of advanced ovarian cancer is often poor. Although there are several treatment options for stage IV epithelial ovarian cancer, it is not clear which treatment will benefit the patient's prognosis.We conducted an analysis using the SEER database to compare the impact of different treatment modalities on the prognosis of advanced ovarian cancer. METHODS: The present study conducts a retrospective analysis of relevant data from the SEER database pertaining to patients diagnosed with stage IV epithelial ovarian cancer between 2011 and 2020 (n = 5345). Statistical methods including Kaplan-Meier curves, log-rank tests, and Cox regression analysis are employed to ascertain the impact of different treatment regimens on the prognosis of patients with stage IV epithelial ovarian cancer. RESULTS: Among patients with stage IV epithelial ovarian cancer, age ≥ 60 and the presence of lung metastases or multiple metastases were identified as poor prognostic factors. Conversely, being Asian or Pacific Islander, married, and testing negative for CA125 were associated with favorable prognoses. In terms of the choice of treatment for patients, surgery plus chemotherapy was the best treatment modality, and timely surgery could significantly improve the prognosis of patients, but there was no difference between chemoradiotherapy alone and the surgery group among patients with lung metastases. CONCLUSION: The prognosis of patients with stage IV epithelial ovarian cancer is influenced by many factors. In terms of the choice of treatment, patients with surgery plus chemotherapy have the best prognosis. In cases where lung metastases are inoperable, a combination of radiotherapy and chemotherapy can be used. In other cases, radiotherapy does not improve outcomes in patients with stage IV epithelial ovarian cancer. This study provides a basis for the choice of treatment for patients with stage IV epithelial ovarian cancer.

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have left a deep impression in the treatment of non-small cell lung cancer (NSCLC), however, not all patients benefit from it. The purpose of this study was to investigate the prognostic value of baseline bone mineral density (BMD) derived from chest computed tomography (CT) scans in NSCLC patients treated with ICIs. Methods: This study included patients with advanced NSCLC who underwent ICI treatment at the Wuhan Union Hospital from March 2020 to October 2022. Baseline BMD was evaluated at non-contrast chest CT at the level of first lumbar vertebra. Patients were divided into BMD-lower group and BMD-higher group according to the optimal cutoff value calculated by X-tile software. Baseline characteristics of the two groups were compared and variables between the two groups were balanced by propensity score matching (PSM) analysis. We calculated the objective response rate (ORR) and disease control rate (DCR) of the two groups and analyzed overall survival (OS) and progression-free survival (PFS) using BMD and other clinical indexes through Cox regression models and Kaplan-Meier survival curves. Results: A total of 479 patients were included in this study, and all patients were divided into BMD-lower group (n=270) and BMD-higher group (n=209). After PSM analysis, each group consisted of 150 patients. ORR (43.3% vs. 43.5% before PSM, P = 0.964; 44.7% vs. 44.7% after PSM, P = 1.000) and DCR (91.1% vs. 94.3% before PSM, P = 0.195; 93.3% vs. 96.7% after PSM, P =0.190) were similar in two groups. There was no statistically significant relationship between BMD degree and PFS before (16.0 months vs. 18.0 months, P = 0.067) and after PSM analysis (17.0 months vs. 19.0 months, P = 0.095). However, lower BMD was associated with shorter OS both before (20.5 months vs. 23.0 months, P< 0.001) and after PSM analysis (20.0 months vs. 23.0 months, P = 0.008). Conclusion: Lower baseline BMD is associated with worse clinical outcomes in NSCLC patients treated with ICIs. As a reliable and easily obtained individual prognostic biomarker, BMD can become a routine detection indicator before immunotherapy.

Mitochondrial metabolism and targeted treatment strategies in ischemic-induced acute kidney injury.

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The kidney is susceptible to IRI under several clinical conditions, including hypotension, sepsis, and surgical procedures, such as partial nephrectomy and kidney transplantation. Extensive research has been conducted on the mechanism and intervention strategies of renal IRI in past decades; however, the complex pathophysiology of IRI-induced AKI (IRI-AKI) is not fully understood, and there remains a lack of effective treatments for AKI. Renal IRI involves several processes, including reactive oxygen species (ROS) production, inflammation, and apoptosis. Mitochondria, the centers of energy metabolism, are increasingly recognized as substantial contributors to the early phases of IRI. Multiple mitochondrial lesions have been observed in the renal tubular epithelial cells (TECs) of IRI-AKI mice, and damaged or dysfunctional mitochondria are toxic to the cells because they produce ROS and release cell death factors, resulting in TEC apoptosis. In this review, we summarize the recent advances in the mitochondrial pathology in ischemic AKI and highlight promising therapeutic approaches targeting mitochondrial dysfunction to prevent or treat human ischemic AKI.

From the regulatory mechanism of TFEB to its therapeutic implications.

Transcription factor EB (TFEB), known as a major transcriptional regulator of the autophagy-lysosomal pathway, regulates target gene expression by binding to coordinated lysosomal expression and regulation (CLEAR) elements. TFEB are regulated by multiple links, such as transcriptional regulation, post-transcriptional regulation, translational-level regulation, post-translational modification (PTM), and nuclear competitive regulation. Targeted regulation of TFEB has been victoriously used as a treatment strategy in several disease models such as ischemic injury, lysosomal storage disorders (LSDs), cancer, metabolic disorders, neurodegenerative diseases, and inflammation. In this review, we aimed to elucidate the regulatory mechanism of TFEB and its applications in several disease models by targeting the regulation of TFEB as a treatment strategy.

Venetoclax combined with decitabine induced tumor lysis syndrome in a young patient with acute myeloid leukemia: a case report and literature review.

Venetoclax, in combination with hypomethylation agents (HMAs), is a novel treatment for leukemia patients with low chemotherapy tolerance. However, it has been reported to be a risk of causing tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL) and elderly acute myeloid leukemia (AML) patients. Here we report a rare case of a young adult AML patient who induced TLS after receiving a combination therapy of venetoclax with decitabine (DEC). A 36-year-old male patient presented with an unexplained fever and was diagnosed with AML-M5a. The patient was first treated with a combination of antibiotics, including voriconazole 300 mg Q12h. After the infection was relieved, he was treated with 100 mg venetoclax in combination with 75 mg/m 2 DEC. However, 12 h after the first treatment, he developed diarrhea, fatigue and other symptoms, and the laboratory results were consistent with the laboratory TLS. The patient stopped chemotherapy immediately, and TLS gradually improved after receiving rehydration, diuresis, dialysis and other treatments. Finally, the patient achieved complete remission. Based on the experience of this case and related studies, we recommend the prevention of TLS should not be limited to elderly patients taking venetoclax, and it is equally important in young patients. And reduce the dosage of venetoclax when using azole antifungal drugs.

Blocking Superantigen-Mediated Diseases: Challenges and Future Trends.

Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vß and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases.

Nuclear Matrix-associated Protein SMAR1 Attenuated Acute Graft-versus-host Disease by Targeting JAK-STAT Signaling in CD4 + T Cells.

BACKGROUND: Acute graft-versus-host disease (aGVHD) mediated by alloreactive T cells remains a serious and life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). The contribution of the different CD4 + T helper cell subtypes to the pathogenesis and regulation of aGVHD is a central point in current research. The specialized effector subsets of T cells that differentiate from naive T cells into mature cells are closely related to scaffold/matrix-associated region-1-binding protein (SMAR1). However, the role of SMAR1 in aGVHD is unclear. METHODS: Peripheral blood was collected from the patients with or without aGVHD after allo-HCT. The differences in CD4 + T cells transduced with the SMAR1 lentivirus vector and empty vector were analyzed. A humanized aGVHD mouse model was constructed to evaluate the function of SMAR1 in aGVHD. RESULTS: The expression of SMAR1 was significantly reduced in the CD4 + T cells from aGVHD patients and related to the occurrence of aGVHD. SMAR1 overexpression in human CD4 + T cells regulated CD4 + T-cell subsets differentiation and inflammatory cytokines secretion and inhibited the Janus kinase/signal transducer and activator of transcription pathway. Moreover, SMAR1 changed chromatin accessibility landscapes and affected the binding motifs of key transcription factors regulating T cells. Additionally, upregulation of SMAR1 expression in CD4 + T cells improved the survival and pathology in a humanized aGVHD mouse model. CONCLUSIONS: Our results showed that upregulation of SMAR1 regulated the CD4 + T-cell subpopulation and cytokines secretion and improved survival in a humanized aGVHD mouse model by alleviating inflammation. This study provides a promising therapeutic target for aGVHD.

ALKHB5-demethylated lncRNA SNHG15 promotes myeloma tumorigenicity by increasing chromatin accessibility and recruiting H3K36me3 modifier SETD2.

Chromatin instability plays a crucial role in multiple myeloma (MM) relapse and progression, but its mechanism remains obscure. Here, we uncovered that m6A-demethylase ALKBH5 upregulated and stabilized long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15), which was elevated in MM and positively correlated with unfavorable clinical prognosis factors. ALKBH5-SNHG15 axis participated in viability and migration/invasion of myeloma cell lines and MM-xenografted SCID/NOD mice. Mechanically, ALKBH5 promoted the expression of trimethylated histone H3 at lysine 36 (H3K36me3) methyltransferase SETD2 through lncRNA SNHG15-mediated protein stability. ALKBH5-SNHG15 axis increased chromatin accessibility and altered the H3K36me3 enrichment at the gene body, which is responsible for transcription elongation. Our study suggested a novel epigenetically interaction of N6-methyladenosine (m6A) methylation, lncRNA SNHG15, and histone SETD2/H3K36me3 modifications in myeloma progression, indicating that ALKBH5 and lncRNA SNHG15 could serve as potential novel therapeutic targets for MM treatment.NEW & NOTEWORTHY To our knowledge, this study first demonstrated the prognostic significance and biological function of long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15) in multiple myeloma (MM), and indicated a novel revelation on the effect of N6-methyladenosine (m6A)-regulated lncRNA on MM tumorigenicity. Moreover, the novel chromatin-regulatory mechanism of lncRNA by interacting with epigenetic modifiers including m6A demethylase ALKBH5 and H3K36me3 methyltransferase SETD2 in myeloma progression elucidated intricate mechanism of tumor pathogenesis.

Single neurons on microelectrode array chip: manipulation and analyses.

Chips-based platforms intended for single-cell manipulation are considered powerful tools to analyze intercellular interactions and cellular functions. Although the conventional cell co-culture models could investigate cell communication to some extent, the role of a single cell requires further analysis. In this study, a precise intercellular interaction model was built using a microelectrode array [microelectrode array (MEA)]-based and dielectrophoresis-driven single-cell manipulation chip. The integrated platform enabled precise manipulation of single cells, which were either trapped on or transferred between electrodes. Each electrode was controlled independently to record the corresponding cellular electrophysiology. Multiple parameters were explored to investigate their effects on cell manipulation including the diameter and depth of microwells, the geometry of cells, and the voltage amplitude of the control signal. Under the optimized microenvironment, the chip was further evaluated using 293T and neural cells to investigate the influence of electric field on cells. An examination of the inappropriate use of electric fields on cells revealed the occurrence of oncosis. In the end of the study, electrophysiology of single neurons and network of neurons, both differentiated from human induced pluripotent stem cells (iPSC), was recorded and compared to demonstrate the functionality of the chip. The obtained preliminary results extended the nature growing model to the controllable level, satisfying the expectation of introducing more elaborated intercellular interaction models.

TEAD4 antagonizes cellular senescence by remodeling chromatin accessibility at enhancer regions.

Dramatic alterations in epigenetic landscapes are known to impact genome accessibility and transcription. Extensive evidence demonstrates that senescent cells undergo significant changes in chromatin structure; however, the mechanisms underlying the crosstalk between epigenetic parameters and gene expression profiles have not been fully elucidated. In the present study, we delineate the genome-wide redistribution of accessible chromatin regions that lead to broad transcriptome effects during senescence. We report that distinct senescence-activated accessibility regions (SAAs) are always distributed in H3K27ac-occupied enhancer regions, where they are responsible for elevated flanking senescence-associated secretory phenotype (SASP) expression and aberrant cellular signaling relevant to SASP secretion. Mechanistically, a single transcription factor, TEAD4, moves away from H3K27ac-labled SAAs to allow for prominent chromatin accessibility reconstruction during senescence. The enhanced SAAs signal driven by TEAD4 suppression subsequently induces a robust increase in the expression of adjacent SASP genes and the secretion of downstream factors, which contribute to the progression of senescence. Our findings illustrate a dynamic landscape of chromatin accessibility following senescence entry, and further reveal an insightful function for TEAD4 in regulating the broad chromatin state that modulates the overall transcriptional program of SASP genes.

Heterogeneous-Nucleation Biosensor for Long-Term Collection and Mask-Based Self-Detection of SARS-CoV-2.

The effective control of infectious diseases, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, depends on the availability of rapid and accurate monitoring techniques. However, conventional SARS-CoV-2 detection technologies do not support continuous self-detection and may lead to cross-infection when utilized in medical institutions. In this study, we introduce a prototype of a mask biosensor designed for the long-term collection and self-detection of SARS-CoV-2. The biosensor utilizes the average resonance Rayleigh scattering intensity of Au nanocluster-aptamers. The inter-mask surface serves as a medium for the long-term collection and concentration enhancement of SARS-CoV-2, while the heterogeneous-nucleation nanoclusters (NCs) contribute to the exceptional stability of Au NCs for up to 48 h, facilitated by the adhesion of Ti NCs. Additionally, the biosensors based on Au NC-aptamers exhibited high sensitivity for up to 1 h. Moreover, through the implementation of a support vector machine classifier, a significant number of point signals can be collected and differentiated, leading to improved biosensor accuracy. These biosensors offer a complementary wearable device-based method for diagnosing SARS-CoV-2, with a limit of detection of 103 copies. Given their flexibility, the proposed biosensors possess tremendous potential for the continuous collection and sensitive self-detection of SARS-CoV-2 variants and other infectious pathogens.

Primary cilia: Structure, dynamics, and roles in cancer cells and tumor microenvironment.

Despite the initiation of tumor arises from tumorigenic transformation signaling in cancer cells, cancer cell survival, invasion, and metastasis also require a dynamic and reciprocal association with extracellular signaling from tumor microenvironment (TME). Primary cilia are the antenna-like structure that mediate signaling sensation and transduction in different tissues and cells. Recent studies have started to uncover that the heterogeneous ciliation in cancer cells and cells from the TME in tumor growth impels asymmetric paracellular signaling in the TME, indicating the essential functions of primary cilia in homeostasis maintenance of both cancer cells and the TME. In this review, we discussed recent advances in the structure and assembly of primary cilia, and the role of primary cilia in tumor and TME formation, as well as the therapeutic potentials that target ciliary dynamics and signaling from the cells in different tumors and the TME.

NLRP14 Safeguards Calcium Homeostasis via Regulating the K27 Ubiquitination of Nclx in Oocyte-to-Embryo Transition.

Sperm-induced Ca2+ rise is critical for driving oocyte activation and subsequent embryonic development, but little is known about how lasting Ca2+ oscillations are regulated. Here it is shown that NLRP14, a maternal effect factor, is essential for keeping Ca2+ oscillations and early embryonic development. Few embryos lacking maternal NLRP14 can develop beyond the 2-cell stage. The impaired developmental potential of Nlrp14-deficient oocytes is mainly caused by disrupted cytoplasmic function and calcium homeostasis due to altered mitochondrial distribution, morphology, and activity since the calcium oscillations and development of Nlrp14-deficient oocytes can be rescued by substitution of whole cytoplasm by spindle transfer. Proteomics analysis reveal that cytoplasmic UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is significantly decreased in Nlrp14-deficient oocytes, and Uhrf1-deficient oocytes also show disrupted calcium homeostasis and developmental arrest. Strikingly, it is found that the mitochondrial Na+ /Ca2+ exchanger (NCLX) encoded by Slc8b1 is significantly decreased in the Nlrp14mNull oocyte. Mechanistically, NLRP14 interacts with the NCLX intrinsically disordered regions (IDRs) domain and maintain its stability by regulating the K27-linked ubiquitination. Thus, the study reveals NLRP14 as a crucial player in calcium homeostasis that is important for early embryonic development.

Complete genome sequences and comparative secretomic analysis for the industrially cultivated edible mushroom Lyophyllum decastes reveals insights on evolution and lignocellulose degradation potential.

Lyophyllum decastes, also known as Luronggu in China, is a culinary edible and medicinal mushroom that was widely cultivated in China in recent years. In the present study, the complete high-quality genome of two mating compatible L. decastes strain was sequenced. The L. decastes LRG-d1-1 genome consists of 47.7 Mb in 15 contigs with a contig N90 of 2.08 Mb and 14,499 predicted gene models. Phylogenetic analysis revealed that L. decastes exhibits a close evolutionary relationship to the Termitomyces and Hypsizygus genus and was diverged from H. marmoreus ~ 45.53 Mya ago. Mating A loci of L. decastes compose of five and four HD genes in two monokaryotic strains, respectively. Mating B loci compose of five STE genes in both two monokaryotic strains. To accelerate the cross-breeding process, we designed four pairs of specific primers and successfully detected both mating types in L. decastes. As a wood-rotting mushroom, a total of 541 genes accounting for 577 CAZymes were identified in the genome of L. decastes. Proteomic analysis revealed that 1,071 proteins including 182 CAZymes and 258 secreted enzymes were identified from four groups (PDB, PDB + bran, PDB + cotton hull, and PDB + sawdust). Two laccases and a quinone reductase were strongly overproduced in lignin-rich cultures, and the laccases were among the top-3 secreted proteins, suggesting an important role in the synergistic decomposition of lignin. These results revealed the robustness of the lignocellulose degradation capacity of L. decastes. This is the first study to provide insights into the evolution and lignocellulose degradation of L. decastes.

Viable Bifidobacterium tablets for the prevention of chemotherapy-/radiation-induced mucositis in patients undergoing haematopoietic stem cell transplantation.

PURPOSE: Mucositis is a frequent and severe complication in haematopoietic stem cell transplantation (HSCT). The effectiveness of probiotics in mucositis has been indicated by several clinical trials, but the results are still controversial. To date, studies on the influence of probiotics in HSCT are limited. Therefore, we conducted this retrospective study to evaluate the impact of viable Bifidobacterium tablets on the incidence and duration of chemotherapy-/radiation-induced mucositis in patients undergoing HSCT. METHODS: Clinical data of 278 patients who underwent HSCT between May 2020 and November 2021 were retrospectively analysed. They were divided into a control group (138) and a probiotic group (140) according to whether they took viable Bifidobacterium tablets. First, we analysed the baseline data of the two groups. Then, we compared the incidence, severity and duration of mucositis between the two groups by using Mann-Whitney U test, chi-square test and Fisher's exact test according to the type of data. In order to exclude the influence of confounding factors, we further evaluated the efficacy of oral probiotics in preventing oral mucositis by Binary logistic regression analysis. RESULTS: The use of viable Bifidobacterium tablets markedly reduced the incidence of oral mucositis (OM) (62.9% vs. 81.2%, p = 0.001) and mainly reduced the incidence of grades 1-2 OM (74.6% vs. 58.6%, p = 0.005). There was no significant difference in the incidence of severe (grades 3-4) OM between the two groups (6.5% vs. 4.3%, p = 0.409). The median duration of OM was shorter in the probiotic group (10 vs. 12 days, p = 0.037). The incidence and duration of diarrhoea did not differ between the two groups. Moreover, the use of viable Bifidobacterium tablets had no influence on engraftment. CONCLUSIONS: Our results suggested that viable Bifidobacterium tablets could effectively reduce the incidence of grades 1-2 OM and duration of OM during the transplant process without affecting the outcome of HSCT.

Biosensors for waterborne virus detection: Challenges and strategies.

Waterborne viruses that can be harmful to human health pose significant challenges globally, affecting health care systems and the economy. Identifying these waterborne pathogens is essential for preventing diseases and protecting public health. However, handling complex samples such as human and wastewater can be challenging due to their dynamic and complex composition and the ultralow concentration of target analytes. This review presents a comprehensive overview of the latest breakthroughs in waterborne virus biosensors. It begins by highlighting several promising strategies that enhance the sensing performance of optical and electrochemical biosensors in human samples. These strategies include optimizing bioreceptor selection, transduction elements, signal amplification, and integrated sensing systems. Furthermore, the insights gained from biosensing waterborne viruses in human samples are applied to improve biosensing in wastewater, with a particular focus on sampling and sample pretreatment due to the dispersion characteristics of waterborne viruses in wastewater. This review suggests that implementing a comprehensive system that integrates the entire waterborne virus detection process with high-accuracy analysis could enhance virus monitoring. These findings provide valuable insights for improving the effectiveness of waterborne virus detection, which could have significant implications for public health and environmental management.

Phototherapy with Cancer-Specific Nanoporphyrin Potentiates Immunotherapy in Bladder Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI. EXPERIMENTAL DESIGN: SV40 T/Ras double-transgenic mice bearing spontaneous bladder cancer and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies. RESULTS: PDT with PNP generated reactive oxygen species, and induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared with 44.8 (P = 0.0123), 52.6 (P = 0.0054), and over 75 (P = 0.0001) days in the anti-programmed cell death-1 antibody (anti-PD-1), PNP PDT, and combination groups, respectively. At Day 75 when all mice in other groups died, only 1 in 7 mice in the combination group died. For the direct anti-tumor activity, compared with the control, the anti-PD-1, PNP PDT, and combination groups induced a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) tumor reduction, respectively. For the abscopal anticancer immunity, the anti-PD-1, PNP PDT, and combination groups induced tumor reduction of 45.73% (P = 0.0001), 54.92% (P < 0.0001), and 75.96% (P < 0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial. CONCLUSIONS: In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.

Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3ß1 integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures Teff cells via the activatable α4ß1 integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

Toxic effects of AZD1208 on mouse oocytes and its possible mechanisms.

AZD1208, a pan-inhibitor that can effectively inhibit PIM kinase, is used for the treatment of advanced solid tumors and malignant lymphomas. Numerous studies have proved its curative effects while its potential cellular toxicity on reproduction was still little known. In this study, we investigated the toxic effects of AZD1208 on mouse oocytes. The results showed that AZD1208 treatment did not affect meiotic resumption, but postponed oocyte maturation as indicated by delayed first polar body extrusion. Further mechanistic study showed that AZD1208 treatment delayed spindle assembly. In addition, we found that oocytes treated with AZD1208 showed mitochondrial dysfunction. Abnormal mitochondrial clusters with decreased mitochondrial membrane potential were observed in oocytes during incubation in vitro. Moreover, increased oxidative stress was observed by testing the level of reactive oxygen species. In summary, our results suggest that AZD1208 treatment influences oocyte meiotic progression by causing mitochondrial dysfunctions and subsequent delayed spindle assembly.

OTSSP167 leads to follicular dysplasia and negatively affects oocyte quality in mice.

OTSSP167 is an anti-tumor drug significantly inhibiting tumor growth in xenotransplantation studies using mouse breast, lung, prostate, and pancreatic cancer cell lines. Its phase I clinical trial has been completed, indicating its great potential for future treatment of solid tumors. However, its drug-related adverse effects on reproductive systems have not yet been reported. In this study, we evaluated the effects of OTSSP167 on reproduction of female mice by determining oocyte quality and follicular development. We selected four-week-old female ICR mice for a 21-day intraperitoneal injection of OTSSP167 at a dose of 5 mg/kg/d. We found that OTSSP167 could block the meiotic process of oocytes, leading to a decrease in oocyte maturation and ovulated oocyte numbers, as well as a decrease in the quality of oocytes. The results showed that OTSSP167 treatment caused disordered spindle assembly, decreased mitochondria membrane potential, and increased accumulation of reactive oxygen species in oocytes. Further investigation showed that OTSSP167 induced DNA double-strand breaks, as indicated by increased levels of γH2AX in oocytes of primordial follicles and granulosa cells of growing follicles, which induced follicular atresia and decreased the numbers of follicles at various growing stages. Our study suggests that OTSSP167 treatment may have serious effects on the ovary and consequences for female cancer patients, providing strong evidence for the necessity of protecting female fertility in clinical OTSSP167 trials.