Ferroptosis, a programmed cell death modality discovered and defined in the last decade, is primarily induced by iron-dependent lipid peroxidation. At present, it has been found that ferroptosis is involved in various physiological functions such as immune regulation, growth and development, aging, and tumor suppression. Especially its role in tumor biology has attracted extensive attention and research. Breast cancer is one of the most common female tumors, characterized by high heterogeneity and complex genetic background. Triple negative breast cancer (TNBC) is a special type of breast cancer, which lacks conventional breast cancer treatment targets and is prone to drug resistance to existing chemotherapy drugs and has a low cure rate after progression and metastasis. There is an urgent need to find new targets or develop new drugs. With the increase of studies on promoting ferroptosis in breast cancer, it has gradually attracted attention as a treatment strategy for breast cancer. Some studies have found that certain compounds and natural products can act on TNBC, promote their ferroptosis, inhibit cancer cells proliferation, enhance sensitivity to radiotherapy, and improve resistance to chemotherapy drugs. To promote the study of ferroptosis in TNBC, this article summarized and reviewed the compounds and natural products that induce ferroptosis in TNBC and their mechanisms of action. We started with the exploration of the pathways of ferroptosis, with particular attention to the System X_c^--cystine-GPX4 pathway and iron metabolism. Then, a series of compounds, including sulfasalazine (SAS), metformin, and statins, were described in terms of how they interact with cells to deplete glutathione (GSH), thereby inhibiting the activity of glutathione peroxidase 4 (GPX4) and preventing the production of lipid peroxidases. The disruption of the cellular defense against oxidative stress ultimately results in the death of TNBC cells. We have also our focus to the realm of natural products, exploring the therapeutic potential of traditional Chinese medicine extracts for TNBC. These herbal extracts exhibit multi-target effects and good safety, and have shown promising capabilities in inducing ferroptosis in TNBC cells. We believe that further exploration and characterization of these natural compounds could lead to the development of a new generation of cancer therapeutics. In addition to traditional chemotherapy, we discussed the role of drug delivery systems in enhancing the efficacy and reducing the toxicity of ferroptosis inducers. Nanoparticles such as exosomes and metal-organic frameworks (MOFs) can improve the solubility and bioavailability of these compounds, thereby expanding their therapeutic potential while minimizing systemic side effects. Although preclinical data on ferroptosis inducers are relatively robust, their translation into clinical practice remains in its early stages. We also emphasize the urgent need for more in-depth and comprehensive research to understand the complex mechanisms of ferroptosis in TNBC. This is crucial for the rational design and development of clinical trials, as well as for leveraging ferroptosis to improve patient outcomes. Hoping the above summarize and review could provide references for the research and development of lead compounds for the treatment for TNBC.

Humans ; Consensus ; Hypersensitivity ; Desensitization, Immunologic/adverse effects* ; Immunotherapy/adverse effects* ; Injections, Subcutaneous ; Allergens

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child ; China/epidemiology* ; Cryptorchidism/genetics* ; Disorders of Sex Development/genetics* ; Female ; Genital Diseases, Male ; Genotype ; Humans ; Hypospadias/genetics* ; Male ; Membrane Proteins/genetics* ; Penis/abnormalities* ; Phenotype ; Retrospective Studies ; Steroid 21-Hydroxylase/genetics*

Abstract: Due to the continued emergence of multiple variants of SARS-CoV-2, the ongoing pandemic has resulted in severe mortality over the past two years. After the Alpha, Beta, Gamma and Delta variants, the most recent new variant of concern (VOC) strain to emerge is Omicron (B.1.1.529), which evolved as a result of the accumulation of a large number of mutations. The Omicron variant, which has a much higher transmission rate than the Delta variant, soon replaced the Delta variant and others, is now the dominant variant worldwide. The emergence of Omicron poses new challenges for the prevention and control of COVID-19 and has raised a number of concerns worldwide. Recently, cases of Omicron infection have been reported in several parts of China, and therefore this paper provides a comprehensive analysis and summary of the epidemiology and immune escape mechanisms of the Omicron variant. We also suggest some therapeutic strategies against the Omicron variant, including rapid diagnosis, genome analysis of emerging variants, ramping up of vaccination drives and receiving booster doses, updating the available vaccines, designing of multivalent vaccines able to generate hybrid immunity, up-gradation of medical facilities and strict implementation of adequate prevention and control measures need to be given high priority to handle the on-going COVID-19 pandemic successfully.

OBJECTIVE: To describe and assess the repair technique and perioperative management for cerebrospinal fluid (CSF) leak resulting from extensive anterior skull base fracture via extradural anterior skull base approach. METHODS: This was a retrospective review conducted at the Department of Neurosurgery of the Shanghai Tenth People's Hospital from January 2015 to April 2020. Patients with traumatic CSF rhinorrhea resulting from extensive anterior skull base fracture treated surgically via extended extradural anterior skull base approach were included in this study. The data of medical and radiological records, surgical approaches, repair techniques, peritoperative management, surgical outcome and postoperative follow-up were analyzed. Surgical repair techniques were tailored to the condition of associated injuries of the scalp, bony and dura injuries and associated intracranial lesions. Patients were followed up for the outcome of CSF leak and surgical complications. Data were presented as frequency and percent. RESULTS: Thirty-five patients were included in this series. The patients' mean age was 33 years (range 11-71 years). Eight patients were treated surgically within 2 weeks; while the other 27 patients, with prolonged or recurrent CSF rhinorrhea, received the repair surgery at 17 days to 10 years after the initial trauma. The mean overall length of follow-up was 23 months (range 3-65 months). All the patients suffered from frontobasal multiple fractures. The basic repair tenet was to achieve watertight seal of the dura. The frontal pericranial flap alone was used in 20 patients, combined with temporalis muscle and/or its facia in 10 patients. Free fascia lata graft was used instead in the rest 5 patients. No CSF leak was found in all the patients at discharge. There was no surgical mortality in this series. Bilateral anosmia was the most common complication. At follow-up, no recurrent CSF leak or meningitis occurred. No patients developed mucoceles, epidural abscess or osteomyelitis. One patient ultimately required ventriculoperitoneal shunt because of progressive hydrocephalus. CONCLUSION Traumatic CSF rhinorrhea associated with extensive anterior skull base fractures often requires aggressive treatment via extended intracranial extradural approach. Vascularized tissue flaps are ideal grafts for cranial base reconstruction, either alone or in combination with temporalis muscle and its fascia---fascia lata sometimes can be opted as free autologous graft. The approach is usually reserved for patients with traumatic CSF rhinorrhea in complex frontobasal injuries.

ObjectiveThis study was to review the efficacy of surgical resections in different clinical situations for a better understanding of the meaning of surgery in the treatment of neuroblastoma (NB).

Data SourcesThe online database ScienceDirect (201-2018) was utilized. The search was conducted using the keywords "neuroblastoma," "neuroblastoma resection," "neuroblastoma surgery," and "high-risk neuroblastoma."

Study SelectionWe retrospectively analyzed of patients who underwent surgical resections in different clinical situations. The article included findings from selected relevant randomized controlled trials, systematic reviews, and meta-analyses or good-quality observational studies. Abstracts only, letters, and editorial notes were excluded. Full-text articles and abstracts were extracted and reviewed to identify key articles discussing surgery management of NB, which were then selected for critical analysis.

ResultsA total of 7800 English language articles were found containing references to NB (201-2018). The 163 articles were searched which were related to the surgical treatment of NB (201-2018). Through the analysis of these important articles, we found that the treatments of NB at low- and intermediate-risk groups were basically the same. High-risk patients remained controversial.

ConclusionsNB prognosis varies tremendously based on the stage and biologic features of the tumor. After reviewing the relevant literature, patients with low-risk disease are often managed with surgical resection or observation alone with tumors likely to spontaneously regress that are not causing symptoms. Intermediate patients are treated with chemotherapy with the number of cycles depending on their response as well as surgical resection of the primary tumor. High-risk patients remain controversial. Multidisciplinary intensive treatment is essential, especially for patients who received subtotal tumor resection. Minimally invasive surgery for the treatment of NBs without image-defined risk factors in low- to high-risk patients is safe and feasible and does not compromise the treatment outcome. We conclude that ≥90% resection of the primary tumor is both feasible and safe in most patients with high-risk NB. New targeted therapies are crucial to improve survival.

Brain Neoplasms ; surgery ; Humans ; Neuroblastoma ; surgery ; Neurosurgical Procedures ; methods ; Prognosis ; Randomized Controlled Trials as Topic ; Retrospective Studies ; Treatment Outcome

BackgroundRecent studies have indicated that autophagy is involved in sepsis-induced myocardial dysfunction. This study aimed to investigate the change of autophagy in cecal ligation and puncture (CLP)-induced myocardium dysfunction and its relationship with mammalian target of rapamycin (mTOR) pathway.

MethodsTotally, 12 rats were randomly divided into CLP group or sham-operated (SHAM) group. Cardiac tissues were harvested 18 h after CLP or sham operation. Pathology was detected by hematoxylin and eosin staining, cardiac functions by echocardiography, distribution of microtubule-associated protein light chain 3 type II (LC3II) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, phosphorylation of mTOR (p-mTOR), phosphorylation of S6 kinase-1 (PS6K1), and LC3II and p62 expression were measured by western blotting. Pearson's correlation coefficient was used to analyze the correlation of two parameters.

ResultsThe results by pathology and echocardiography revealed that there was obvious myocardial injury in CLP rats (left ventricle ejection fraction: SHAM 0.76 ± 0.06 vs. CLP 0.59 ± 0.11, P < 0.01; fractional shortening: SHAM 0.51 ± 0.09 vs. CLP 0.37 ± 0.06, P < 0.05). We also found that the autophagy process was elevated by CLP, the ratio of LC3II/LC3I was increased (P < 0.05) while the expression of p62 was decreased (P < 0.05) in the CLP rats, and there were also more autophagosomes and autolysosomes in the CLP rats. Furthermore, the mTOR pathway in CLP myocardium was inhibited when compared with the sham-operated rats; p-mTOR (P < 0.01) and PS6K1 (P < 0.05) were both significantly suppressed following CLP challenge. Interestingly, we found that the mTOR pathway was closely correlated with the autophagy processes. In our study, while p-mTOR in the myocardium was significantly correlated with p62 (r = 0.66, P = 0.02), PS6K1 was significantly positively correlated with p62 (r = 0.70, P = 0.01) and negatively correlated with LC3II (r = -0.71, P = 0.01).

ConclusionsThe autophagy process in the myocardium was accelerated in CLP rats, which was closely correlated with the inhibition of the mTOR pathway.

Animals ; Autophagy ; physiology ; Cecum ; injuries ; Echocardiography ; Immunohistochemistry ; Ligation ; Male ; Microscopy, Electron, Transmission ; Myocardium ; metabolism ; Rats ; Rats, Wistar ; Sepsis ; metabolism ; TOR Serine-Threonine Kinases ; metabolism

Aim To investigate the expression of CAR-MA3, NF-κB in hepatocellular carcinoma tissues and the underlying mechanism of sodium aescinate in inhib-iting the proliferation of human hepatocellular carcino-ma cells. Methods The expression of CARMA3 and NF-κB in HCC tissues were detected by tissue microar-ray immunohistochemistry. MTT was used to determine the effect of sodium aescinate on the proliferation of HCC cells. Cell apoptosis was detected by flow cytom-etry. The expression of CARMA3, NF-κB protein in HepG2 and Hep3B cells treated with sodium aescinate was detected by Western blot and cell immunofluores-cence. Results Tissue microarray analysis showed that the expression of CARMA3 in HCC was up-regulated compared with the adjacent adjacent liver tissues, and the histopathological differentiation, TNM stage, tumor volume and prognosis were correlated. Sodium aesci-nate in 40 μmol·L-1concentration ( IC50) inhibited the growth of HCC cell lines, promoting its apoptosis, but without toxic effects on normal liver cells. Western blot and cell immunofluorescence detection of sodium aescinate could significantly inhibit the expression of CARMA3 and NF-κB. Conclusion Sodium aescinate can effectively inhibit the proliferation of HCC cells by inhibiting the activation of CARMA3/NF-κB signaling in HCC.

The response surface method was used to evaluate the concentration range, property and degree of Scutellaria (HQ) and Coptis (HL) herb pair on improvement of glucose and lipid metabolism in this paper. Type 2 diabetes mellitus (T2DM) was induced in rats by low a dose of streptozotocin (STZ) in combination with high-fat diet feeding. The rats were administered with HQ-HL extract pairs at different ratio (1:0, 3:1, 2:1, 3:2, 1:1, 2:3, 1:2, 1:3, 0:1). To investigate the influence of herb pair extracts on glucose and lipid metabolism of T2DM rats, the multi index synthetic index method was adopted to integrate the indexes, then the response surface method was applied to analyze the integration results. The ratio of HQ and HL from 3:1 to 1:3 showed a synergistic effect (with the value between -0.2 and -0.8). Especially, when the proportion was between 3:2 and 1:3, herb pair extracts possessed stronger synergistic effects (value:-0.8). The high dose of HQ-HL with the ratio of 1:1 exhibited the strongest synergistic effect.

BACKGROUNDTriggering receptor expressed on myeloid cell-1 (TREM-1) may play a vital role in mammalian target of rapamycin (mTOR) modulation of CD8+ T-cell differentiation through the transcription factors T-box expressed in T-cells and eomesodermin during the immune response to invasive pulmonary aspergillosis (IPA). This study aimed to investigate whether the mTOR signaling pathway modulates the proliferation and differentiation of CD8+ T-cells during the immune response to IPA and the role TREM-1 plays in this process.

METHODSCyclophosphamide (CTX) was injected intraperitoneally, and Aspergillus fumigatus spore suspension was inoculated intranasally to establish the immunosuppressed IPA mouse model. After inoculation, rapamycin (2 mg.kg-1.d-1) or interleukin (IL)-12 (5 μg/kg every other day) was given for 7 days. The number of CD8+ effector memory T-cells (Tem), expression of interferon (IFN)-γ, mTOR, and ribosomal protein S6 kinase (S6K), and the levels of IL-6, IL-10, galactomannan (GM), and soluble TREM-1 (sTREM-1) were measured.

RESULTSViable A. fumigatus was cultured from the lung tissue of the inoculated mice. Histological examination indicated greater inflammation, hemorrhage, and lung tissue injury in both IPA and CTX + IPA mice groups. The expression of mTOR and S6K was significantly increased in the CTX + IPA + IL-12 group compared with the control, IPA (P = 0.01; P= 0.001), and CTX + IPA (P = 0.034; P= 0.032) groups, but significantly decreased in the CTX + IPA + RAPA group (P < 0.001). Compared with the CTX + IPA group, the proportion of Tem, expression of IFN-γ, and the level of sTREM-1 were significantly higher after IL-12 treatment (P = 0.024, P= 0.032, and P= 0.017, respectively), and the opposite results were observed when the mTOR pathway was blocked by rapamycin (P < 0.001). Compared with the CTX + IPA and CTX + IPA + RAPA groups, IL-12 treatment increased IL-6 and downregulated IL-10 as well as GM, which strengthened the immune response to the IPA infection.

CONCLUSIONSmTOR modulates CD8+ T-cell differentiation during the immune response to IPA. TREM-1 may play a vital role in signal transduction between mTOR and the downstream immune response.

Animals ; CD8-Positive T-Lymphocytes ; cytology ; metabolism ; Cell Differentiation ; genetics ; physiology ; Female ; Interferon-gamma ; metabolism ; Invasive Pulmonary Aspergillosis ; metabolism ; Lymphocyte Activation ; genetics ; physiology ; Mice ; Mice, Inbred BALB C ; Myeloid Cells ; cytology ; metabolism ; Ribosomal Protein S6 Kinases ; metabolism ; TOR Serine-Threonine Kinases ; genetics ; metabolism ; Tissue Culture Techniques