Macrophages modulate fibrosis during newt lens regeneration.

BACKGROUND: Previous studies have suggested that macrophages are present during lens regeneration in newts, but their role in the process is yet to be elucidated. METHODS: Here we generated a transgenic reporter line using the newt, Pleurodeles waltl, that traces macrophages during lens regeneration. Furthermore, we assessed early changes in gene expression during lens regeneration using two newt species, Notophthalmus viridescens and Pleurodeles waltl. Finally, we used clodronate liposomes to deplete macrophages during lens regeneration in both species and tested the effect of a subsequent secondary injury after macrophage recovery. RESULTS: Macrophage depletion abrogated lens regeneration, induced the formation of scar-like tissue, led to inflammation, decreased iris pigment epithelial cell (iPEC) proliferation, and increased rates of apoptosis in the eye. Some of these phenotypes persisted throughout the last observation period of 100 days and could be attenuated by exogenous FGF2 administration. A distinct transcript profile encoding acute inflammatory effectors was established for the dorsal iris. Reinjury of the newt eye alleviated the effects of macrophage depletion, including the resolution of scar-like tissue, and re-initiated the regeneration process. CONCLUSIONS: Together, our findings highlight the importance of macrophages for facilitating a pro-regenerative environment in the newt eye by regulating fibrotic responses, modulating the overall inflammatory landscape, and maintaining the proper balance of early proliferation and late apoptosis of the iPECs.

Case report: Prostatic malakoplakia: a rare disease that has a profile mimicking prostate cancer.

Prostatic malakoplakia (PMP) is a rare inflammatory disease, and misdiagnosis on imaging is a major reason for unnecessary punctures; however, information on imaging is even rarer. Five patients with PMP between May 2022 and February 2023 were enrolled in this study to summarize the imaging manifestations. All patients underwent ultrasound (US)-guided prostate biopsy and were confirmed by pathology, and the presence of prostate cancer was also excluded by pathology. The five patients, with a median age of 71 years (range = 58-74 years), had a median total prostate-specific antigen (T-PSA) of 10.40 ng/mL (range = 1.74-63.42 ng/mL). In two patients, chest computed tomography showed pulmonary infections. All patients underwent magnetic resonance imaging (MRI). Of these patients, four had a Prostate Imaging-Reporting and Data System (PIRADS) score of 5, while one had a score of 4. The lesions were mostly distributed in the peripheral zone of the prostate and appeared as a high signal on T1-weighted imaging (T1WI) and a low signal on T2-weighted imaging (T2WI). In the US examination, four patients had abnormal prostate morphology, with an unsmooth envelope and non-uniform parenchymal echogenicity. Four patients had increased prostate volume. US showed a hypoechoic nodule with non-uniform internal echogenicity, and an abundant internal blood flow signal was detected by color Doppler US. PSA, MRI, and US were not specific for PMP in our study, but we found that a history of co-infection may be helpful in an accurate diagnosis and to avoid unnecessary biopsy.

Measurable residual disease monitoring by ddPCR in the early posttransplant period complements the traditional MFC method to predict relapse after HSCT in AML/MDS: a multicenter retrospective study.

BACKGROUND: Droplet digital PCR (ddPCR) is widely applied to monitor measurable residual disease (MRD). However, there are limited studies on the feasibility of ddPCR-MRD monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially targeting multiple molecular markers simultaneously. METHODS: Our study collected samples from patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in complete remission after allo-HSCT between January 2018 and August 2021 to evaluate whether posttransplant ddPCR-MRD monitoring can identify patients at high risk of relapse. RESULTS: Of 152 patients, 58 (38.2%) were MRD positive by ddPCR within 4 months posttransplant, with a median variant allele frequency of 0.198%. The detectable DTA mutations (DNMT3A, TET2, and ASXL1 mutations) after allo-HSCT were not associated with an increased risk of relapse. After excluding DTA mutations, patients with ddPCR-MRD positivity had a significantly higher cumulative incidence of relapse (CIR, 38.7% vs. 9.7%, P < 0.001) and lower rates of relapse-free survival (RFS, 55.5% vs. 83.7%, P < 0.001) and overall survival (OS, 60.5% vs. 90.5%, P < 0.001). In multivariate analysis, ddPCR-MRD positivity of non-DTA genes was an independent adverse predictor for CIR (hazard ratio [HR], 4.02; P < 0.001), RFS (HR, 2.92; P = 0.002) and OS (HR, 3.12; P = 0.007). Moreover, the combination of ddPCR with multiparameter flow cytometry (MFC) can further accurately identify patients at high risk of relapse (F+/M+, HR, 22.44; P < 0.001, F+/M-, HR, 12.46; P < 0.001 and F-/M+, HR, 4.51; P = 0.003). CONCLUSION: ddPCR-MRD is a feasible approach to predict relapse after allo-HSCT in AML/MDS patients with non-DTA genes and is more accurate when combined with MFC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06000306. Registered 17 August 2023 -Retrospectively registered ( https://clinicaltrials.gov/study/NCT06000306?term=NCT06000306&rank=1 ).

[Application Progress of Shared Decision Making Model in Patients
with Thoracic Cancer].

As a new diagnosis and treatment decision-making model, shared decision making (SDM) can effectively solve the problem of patient compliance in the diagnosis and treatment of thoracic tumors, balance the status of both doctors and patients, and gradually get attention and application in the clinical practice of thoracic surgery. The application of SDM in the diagnosis and treatment of thoracic tumors is conducive to improve doctors' diagnosis and treatment level and alleviating the pressure of responsibility, reduce patients' psychological pressure and improve patients' compliance and also improve medical trust and reduce doctor-patient conflict. Due to the limited medical literacy and autonomy of patients, the time for diagnosis and treatment is short due to the imbalance of doctor-patient ratio. Meanwhile, due to the limited sample size of existing studies, SDM model cannot be proved to have a clear gain for the treatment of thoracic tumors, and the implementation of SDM model still faces resistance. In the future, the development of auxiliary decision-making system and the improvement of doctors' humanistic care ability will be conducive to promote the practical application of SDM model in thoracic surgery.
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TP53 in MDS and AML: Biological and clinical advances.

Recently, the WHO-5 and the ICC 2022 criteria have emphasized poor prognosis in AML/MDS patients with multi-hit TP53 mutations, whereas mutated TP53 plays a critical role in tumorigenesis, drawing substantial interest in exploring its biological behaviors. Diverse characteristics of TP53 mutations, including types, VAF, CNVs, allelic status, karyotypes, and concurrent mutations have been extensively studied. Novel potential targets and comprehensive treatment strategies nowadays are under swift development, owing to great advances in technology. However, accurately predicting prognosis of patients with TP53-mutated myeloid neoplasms remains challenging. And there is still a lack of effective treatment for those patients.

Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer.

Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

Nanoscale metal-organic framework delivers rapamycin to induce tissue immunogenic cell death and potentiates cancer immunotherapy.

Rapamycin has great potential in the antitumor application, but its therapeutic effect is seriously affected by poor water solubility, targeting ability, and low bioavailability. Here, we constructed a novel composite nanomaterial with PCN-224 as a drug carrier and loaded rapamycin, named R@BP@HA. The nanoplate not only improves targeting, but also synergizes rapamycin with PCN-224 to effectively promote tumor cell apoptosis, which subsequently causes immunogenic cell death (ICD), and shows strong therapeutic effect in 4T1 breast cancer model. The treatment effect depends on three main points:(i)Proapoptotic effect of rapamycin on tumor cells;(ii)ROS production by PCN-224-mediated photodynamic therapy;(iii)ICD induced DC maturation, increased immune response and promoted T cell proliferation and differentiation. This nanoplate offers potential antitumor efficacy in combination with chemotherapy, photodynamic therapy, and immunotherapy.

Efficacy of Immunization against a Novel Synthetic 13-Amino Acid Betaglycan-Binding Peptide Sequence of Inhibin α Subunit on Promoting Fertility in Female Rats.

Inhibins suppress the FSH production in pituitary gonadotrope cells by robustly antagonizing activin signaling by competitively binding to activin type II receptors (ACTR II). The binding of inhibin A to ACTR II requires the presence of its co-receptor, namely, betaglycan. In humans, the critical binding site for betaglycan to inhibin A was identified on the inhibin α subunit. Through conservation analysis, we found that a core 13-amino-acid peptide sequence within the betaglycan-binding epitope on human inhibin α subunit is highly conserved across species. Based on the tandem sequence of such a conserved 13-amino-acid betaglycan-binding epitope (INHα13AA-T), we developed a novel inhibin vaccine and tested its efficacy in promoting female fertility using the female rat as a model. Compared with placebo-immunized controls, INHα13AA-T immunization induced a marked (p < 0.05) antibody generation, enhanced (p < 0.05) ovarian follicle development, and increased ovulation rate and litter sizes. Mechanistically, INHα13AA-T immunization promoted (p < 0.05) pituitary Fshb transcription and increased (p < 0.05) serum FSH and 17ß-estradiol concentrations. In summary, active immunization against INHα13AA-T potently increased FSH levels, ovarian follicle development, ovulation rate and litter sizes, thus causing super-fertility in females. Therefore, immunization against INHα13AA is a promising alternative to the conventional approach of multiple ovulation and super-fertility in mammals.

The comparison of the Effect of double reverse traction repositor (DRTR) and traction table assisted Anterograde Intramedullary nail in treatment of femoral shaft fractures.

OBJECTIVE: The objective of this study was to compare the clinical efficacy of DRTR (Double Reverse Traction Repositor, DRTR)and traction table in the treatment of femoral shaft fractures with the aid of AN-IMN (Antegrade intramedullary nailing). PATIENTS AND METHODS: In this study, patients with femoral shaft fractures admitted to the Department of Orthopedics at Zhaoqing First People's Hospital from May 2018 to October 2022 were recruited. All patients were treated with anterograde intramedullary nailing, with 23 patients in the DRTR-assisted group and 21 patients in the traction table-assisted group. The demographic characteristics, fracture classification, intraoperative data, postoperative data, and prognostic indicators of the two groups were recorded and analyzed retrospectively. All procedures were performed by the same team of experienced physicians. RESULTS: All the patients in the two groups were followed up for more than 12 months. Both traction methods could provide stable traction for the operator during AN-IMN, and there was no significant difference in demographic characteristics and fracture classification. The intraoperative fluoroscopy times and opening reduction rate of the DRTR group were lower than those of the traction table group (P < 0.05), and the postoperative Harris Hip Score, as well as the Lyshol Lysholm knee function Score of the DRTR group, were significantly higher than the traction table group members (P < 0.05). Postoperative complications such as perineal soft tissue injury and lateral femoral cutaneous nerve injury occurred in the traction table group, but not in the DRTR group. CONCLUSION: DRTR can safely and effectively provide continuous and stable traction in the femoral shaft fractures surgery, and outperforms the traction table in the number of intraoperative fluoroscopy, opening reduction rate, reduction of complications, and postoperative joint function score.

An arabinogalactan isolated from Pollen Typhae induces the apoptosis of RKO cells by promoting macrophage polarization.

An arabinogalactan (PTPS-1-2) was isolated and characterized from Pollen Typhae, and its potential antitumor effects on activating macrophages to produce immunomodulatory factors and promoting apoptosis in colorectal cancer cells were investigated. Structural characterization showed that PTPS-1-2 had a molecular weight of 59 kDa and was composed of rhamnose, arabinose, glucuronic acid, galactose, and galacturonic acid with a molar ratio of 7.6: 17.1: 6.5: 61.4: 7.4. Its backbone was predominantly composed of T-ß-D-Galp, 1,3-ß-D-Galp, 1,6-ß-D-Galp, 1,3,6-ß-D-Galp, 1,4-α-D-GalpA, 1,2-α-L-Rhap, additionally, branches contained 1,5-α-L-Araf, T-α-L-Araf, T-ß-D-4-OMe-GlcpA, T-ß-D-GlcpA and T-α-L-Rhap. PTPS-1-2 activated RAW264.7 cell by triggering the NF-kB signaling pathway and M1 macrophage polarization. Furthermore, the conditioned medium (CM) of Mφ pretreated with PTPS-1-2 exerted marked antitumor effects by inhibiting RKO cell proliferation and suppressing cell colony formation. Collectively, our findings suggested that PTPS-1-2 might be a therapeutic option for the prevention and treatment of tumors.

Mortality Evaluation and Life Expectancy Prediction of Patients with Hepatocellular Carcinoma with Data Mining.

BACKGROUND: The complexity of systemic variables and comorbidities makes it difficult to determine the best treatment for patients with hepatocellular carcinoma (HCC). It is impossible to perform a multidimensional evaluation of every patient, but the development of guidelines based on analyses of said complexities would be the next best option. Whereas conventional statistics are often inadequate for developing multivariate predictive models, data mining has proven more capable. Patients, methods and findings: Clinical profiles and treatment responses of 537 patients diagnosed with Barcelona Clinic Liver Cancer stages B and C from 2009 to 2019 were retrospectively analyzed using 4 decision tree algorithms. A combination of 19 treatments, 7 biomarkers, and 4 states of hepatitis was tested to determine which combinations would result in survival times greater than a year in duration. Just 2 of the algorithms produced complete models through single trees, which made them only the ones suitable for clinical judgement. A combination of alpha fetoprotein ≤210.5 mcg/L, glutamic oxaloacetic transaminase ≤1.13 µkat/L, and total bilirubin ≤ 0.0283 mmol/L was shown to be a good predictor of survival >1 year, and the most effective treatments for such patients were radio-frequency ablation (RFA) and transarterial chemoembolization (TACE) with radiation therapy (RT). In patients without this combination, the best treatments were RFA, TACE with RT and targeted drug therapy, and TACE with targeted drug therapy and immunotherapy. The main limitation of this study was its small sample. With a small sample size, we may have developed a less reliable model system, failing to produce any clinically important results or outcomes. CONCLUSION: Data mining can produce models to help clinicians predict survival time at the time of initial HCC diagnosis and then choose the most suitable treatment.

Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.

Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.

In Vivo and Ex Vivo View of Newt Lens Regeneration.

Lens regeneration in the adult newt illustrates a unique example of naturally occurring cell transdifferentiation. During this process, iris pigmented epithelial cells (iPECs) reprogram into a lens, a tissue that is derived from a different embryonic source. Several methodologies both in vivo and in culture have been utilized over the years to observe this phenomenon. Most recently, Optical Coherence Tomography (OCT) has been identified as an effective tool to study the lens regeneration process in continuity through noninvasive, real-time imaging of the same animal. Described in this chapter are three different methodologies that can be used to observe the newt lens regeneration process both in vivo and ex vivo.

Indole diketopiperazine alkaloids and aromatic polyketides from the Antarctic fungus Penicillium sp. SCSIO 05705.

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2-5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7-10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1-12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 µM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.

A glyoxylate-containing benzene derivative and butenolides from a marine algicolous fungus Aspergillus sp. SCSIO 41304.

A new glyoxylate-containing benzene derivative, methyl 2-(4-hydroxy-3-(3'-methyl-2'-butenyl)phenyl)-2-oxoacetate (1), together with ten known compounds (2-11), were isolated from the marine algicolous fungus, Aspergillus sp. SCSIO 41304. Their planar structures and absolute configurations were elucidated by detailed NMR, MS spectroscopic analysis and comparing with literature data. Compound 1 was isolated as a new fungal secondary metabolite, possessing a methyl glyoxylate moiety R-CO-CO-OCH3, which is rare in natural sources. All the isolated compounds (1-11) were tested for their antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among these compounds, aspulvinone H (4) showed moderate inhibition against AChE and PL with IC50 values of 25.95 and 47.06 µM, respectively. Further molecular docking simulation exhibited that compound 4 could well bind to the catalytic pockets of the AChE and PL.

Expression analysis of TLR signaling pathway genes under lipopolysaccharide-induced and E. coli F17-infected sheep intestinal epithelial cells.

Escherichia coli (E. coli) F17 is one of the main pathogens causing diarrhea in young livestock. The specific F17 fimbriae and lipopolysaccharide (LPS) in the surface components of E. coli F17 induces immune activation via interacting with the intestinal epithelial cells (IECs)-expressed innate immune toll-like receptors (TLRs) signaling pathway. In this study, the expression patterns of eight canonical genes from the TLR signaling pathway (IL-6, IL-8, IL-1ß, TLR4, MyD88, CD14, TNF-α and TRAF6) were analyzed in LPS-induced IECs, E. coli F17-infected IECs and ileum tissue of E. coli F17-infected lambs. The results showed that increased expression levels of all the studied genes were observed following post-LPS-induced and E. coli F17-infected treatment, with TLR4 having the highest up-regulated expression multiple (compared to NC, fold change = 17.94 and 20.11, respectively), and CD14 having the lowest up-regulated expression multiple (fold change = 2.68 and 1.59, respectively), and higher expression levels of all the studied TLR signaling pathway genes were observed in ileum tissue of E. coli F17 antagonistic (AN) lambs than in E. coli F17 sensitive (SE) lambs. Furthermore, when compared to LPS-induced IECs, E. coli F17-infected IECs showed a more pronounced increase in the expression of IL6, TLR4 and TNF-α, indicating the different roles of these genes in the IECs resistance to E. coli F17 infection. Our results demonstrate that the TLR signaling pathway likely promotes immune activation and provide the first evidence that TLRs have a significant potential to protect against E. coli F17 infections.

Lipid metabolism regulatory activity and adverse effects of fungi-derived butyrolactone I.

Butyrolactone I (BTL-I), a butenolide compound isolated from land or marine-derived fungi, has been reported to show diverse activities. To further study the pharmaceutical potential of BTL-I, transcriptome and bioinformatics analysis of BTL-I treated HepG2 cells were taken. BTL-I was revealed with lipid metabolism regulatory activity and confirmed by increasing the mRNA expression of related genes, such as LXRα and its target gene UGT1A1. However, the obvious chemical carcinogenesis of BTL-I was also disclosed. BTL-I could significantly increase the mRNA and protein levels of oncogenes such as CYP1A1. Molecular docking of BTL-I and its analogs were performed to understand the active or toxic effects. Although BTL-I showed attractive activities, enough attention must be paid to its adverse effects in its further development.