MyD88 signaling pathways: role in breast cancer.

MyD88 plays a central role in breast cancer, exerting a multitude of effects that carry substantial implications. Elevated MyD88 expression is closely associated with aggressive tumor characteristics, suggesting its potential as a valuable prognostic marker and therapeutic target. MyD88 exerts influence over several critical aspects of breast cancer, including metastasis, recurrence, drug resistance, and the regulation of cancer stem cell properties. Furthermore, MyD88 modulates the release of inflammatory and chemotactic factors, thereby shaping the tumor's immune microenvironment. Its role in immune response modulation underscores its potential in influencing the dynamic interplay between tumors and the immune system. MyD88 primarily exerts intricate effects on tumor progression through pathways such as Phosphoinositide 3-kinases/Protein kinase B (PI3K/Akt), Toll-like Receptor/Nuclear Factor Kappa B (TLR/NF-κB), and others. Nevertheless, in-depth research is essential to unveil the precise mechanisms underlying the diverse roles of MyD88 in breast cancer. The translation of these findings into clinical applications holds great promise for advancing precision medicine approaches for breast cancer patients, ultimately enhancing prognosis and enabling the development of more effective therapeutic strategies.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

An machine learning model to predict quality of life subtypes of disabled stroke survivors.

OBJECTIVE: Stroke causes serious physical disability with impaired quality of life (QoL) and heavy burden on health. The goal of this study is to explore the impaired QoL typologies and their predicting factors in physically disabled stroke survivors with machine learning approach. METHODS: Non-negative matrix factorization (NMF) was applied to clustering 308 physically disabled stroke survivors in rural China based on their responses on the short form 36 (SF-36) assessment of quality of life. Principal component analysis (PCA) was conducted to differentiate the subtypes, and the Boruta algorithm was used to identify the variables relevant to the categorization of two subtypes. A gradient boosting machine(GBM) and local interpretable model-agnostic explanation (LIME) algorithms were used to apply to interpret the variables that drove subtype predictions. RESULTS: Two distinct subtypes emerged, characterized by short form 36 (SF-36) domains. The feature difference between worsen QoL subtype and better QoL subtype was as follows: role-emotion (RE), body pain (BP) and general health (GH), but not physical function (PF); the most relevant predictors of worsen QoL subtypes were help from others, followed by opportunities for community activity and rehabilitation needs, rather than disability severity or duration since stroke. INTERPRETATION: The results suggest that the rehabilitation programs should be tailored toward their QoL clustering feature; body pain and emotional-behavioral problems are more crucial than motor deficit; stroke survivors with worsen QoL subtype are most in need of social support, return to community, and rehabilitation.

Development of Polyvinyl Alcohol/Polyethylene Glycol Copolymer-based Orodispersible Films Loaded with Entecavir: Formulation and In vitro Characterization.

PURPOSE: The aim of the study is to prepare entecavir (ETV)-loaded orodispersible films (ODFs) using polyvinyl alcohol (PVA)/polyethylene glycol (PEG) graft copolymer (Kollicoat® IR) as a film-forming agent, and further to evaluate the dissolution rate, mechanical and physicochemical properties of films. METHODS: ETV-ODFs were prepared by a solvent casting method. The amount of film-forming agent, plasticizer, and disintegrating agent was optimized in terms of the appearance, thickness, disintegration time and mechanical properties of ODFs. The compatibility between the drug and each excipient was conducted under high temperature (60 °C), high humidity (RH 92.5%), and strong light (4500 Lx) for 10 days. The dissolution study of optimal ODFs compared with the original commercial tablet (Baraclude®) was performed using a paddle method in pH 1.0, pH 4.5, pH 6.8, and pH 7.4 media at 37 °C. The morphology of ODFs was observed via scanning electron microscopy (SEM). The mechanical properties such as tensile strength (TS), elastic modulus (EM), and percentage elongation (E%) of ODFs were evaluated using the universal testing machine. The physicochemical properties of ODFs investigated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR). RESULTS: The related substances were less than 0.5% under high temperature, high humidity, and strong light for 10 days when ETV was mixed with excipients. The optimal formulation of ODFs was set as the quality ratio of Kollicoat® IR, glycerol, sodium alginate (ALG-Na): TiO2: MCC+CMC-Na: ETV was 60:9:12:1:1:1. The drug-loaded ODFs were white and translucent with excellent stripping property. The thickness, disintegration time, EM, TS, and E% were 103.33±7.02 µm, 25.31±1.95 s, 25.34±8.69 Mpa, 2.14±0.26 Mpa, and 65.45±19.41 %, respectively. The cumulative drug release from ODFs was more than 90% in four different media at 10 min. The SEM showed that the drug was highly dispersible in ODFs, and the XRD, DSC, and FT-IR results showed that there occurred some interactions between the drug and excipients. CONCLUSION: In conclusion, the developed ETV-loaded ODFs showed relatively short disintegration time, rapid drug dissolution, and excellent mechanical properties. This might be an alternative to conventional ETV Tablets for the treatment of chronic hepatitis B.

Cuproptosis and cuproptosis-related genes: Emerging potential therapeutic targets in breast cancer.

Breast cancer is one of the most common malignant tumors in women worldwide, and thus, it is important to enhance its treatment efficacy [1]. Copper has emerged as a critical trace element that affects various intracellular signaling pathways, gene expression, and biological metabolic processes [2], thereby playing a crucial role in the pathogenesis of breast cancer. Recent studies have identified cuproptosis, a newly discovered type of cell death, as an emerging therapeutic target for breast cancer treatment, thereby offering new hope for breast cancer patients. Tsvetkov's research has elucidated the mechanism of cuproptosis and uncovered the critical genes involved in its regulation [3]. Manipulating the expression of these genes could potentially serve as a promising therapeutic strategy for breast cancer treatment. Additionally, using copper ionophores and copper complexes combined with nanomaterials to induce cuproptosis may provide a potential approach to eliminating drug-resistant breast cancer cells, thus improving the therapeutic efficacy of chemotherapy, radiotherapy, and immunotherapy and eventually eradicating breast tumors. This review aims to highlight the practical significance of cuproptosis-related genes and the induction of cuproptosis in the clinical diagnosis and treatment of breast cancer. We examine the potential of cuproptosis as a novel therapeutic target for breast cancer, and we explore the present challenges and limitations of this approach. Our objective is to provide innovative ideas and references for the development of breast cancer treatment strategies based on cuproptosis.

Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.

OBJECTIVE: To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer. DESIGN: Randomised, double blind, placebo controlled, multicentre, phase 3 trial. SETTING: 40 centres in China between 6 May 2019 and 17 January 2022. PARTICIPANTS: 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer. INTERVENTIONS: Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival as assessed by the investigator. RESULTS: Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up. CONCLUSIONS: Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03863223.

Real-world treatment patterns and outcomes of pyrotinib-based therapy in patients with HER2-positive advanced breast cancer (PRETTY): A nationwide, prospective, observational study.

Pyrotinib, an irreversible pan-ErbB inhibitor, has been approved for treating HER2-positive advanced breast cancer in China. We conducted a nationwide, prospective observational study to examine the real-world data of pyrotinib-based therapy in this population. Patients from 61 sites across China were included. Pyrotinib-based regimens were prescribed at local physician's discretion. Demographics, treatment patterns, prognosis and safety were evaluated. The primary outcome was real-world progression-free survival (rwPFS). Of 1129 patients, pyrotinib-based therapy was prescribed as first-, second- and third- or later-line treatment in 437 (38.7%), 476 (42.2%) and 216 (19.1%) patients, respectively. Median rwPFS (mrwPFS) was 14.3 (95% CI, 13.3-15.2) months in the total population, with the longest mrwPFS of 17.8 (95% CI, 15.2-24.9) months in the first-line setting, followed by 14.4 (95% CI, 12.9-15.3) months in the second-line setting. Patients with third- or later-line treatment also achieved a mrwPFS of 9.3 (95% CI, 8.4-11.8) months. Patients with trastuzumab- or trastuzumab-pertuzumab-treated disease achieved a mrwPFS of 14.3 and 13.6 months, respectively. Dual HER2 blockade with pyrotinib plus trastuzumab showed a mrwPFS of 16.2 months in the total population, with data not mature in the first-line setting. For patients with baseline brain metastases, the mrwPFS was 11.7 months. The most common adverse event was diarrhea (any grade, 73.5%; grade ≥ 3, 15.3%). In real world, pyrotinib-based therapy shows promising effectiveness in the first-, as well as second- and later-line treatment, with acceptable tolerability. Further investigations regarding front-line use or novel combinations of pyrotinib might facilitate to maximize its anti-tumor potential.

Flavonoid Synthesis by Deinococcus sp. 43 Isolated from the Ginkgo Rhizosphere.

Flavonoids are crucial in physiological and pharmaceutical processes, especially the treatment of cancer and the prevention of cardiovascular and cerebrovascular diseases. Flavonoid-producing plants and fungi have been extensively reported, but bacteria have been much less investigated as a source of flavonoid production. Deinococcus sp. 43, a spherical flavonoid-producing bacteria from the Ginkgo rhizosphere, was reported in this study. First, the whole genome of Deinococcus sp. 43 was sequenced and a series of flavonoid anabolic genes were annotated. Simultaneously, High Performance Liquid Chromatography (HPLC) results showed that Deinococcus sp. 43 was capable of producing flavonoids, with a maximum quercetin output of 2.9 mg/L. Moreover, the relative expression of key genes involved in flavonoid synthesis was determined to test the completeness of the flavonoid anabolic pathway. The results of LC-MS analysis demonstrated that the flavonoids produced by Deinococcus sp. 43 were significantly different between intracellular and extracellular environments. The concentration of multiple glycosylated flavonoids was substantially higher in extracellular than intracellular environments, while the majority of flavonoids obtained in intracellular environments were hydroxylated multiple times. Lastly, the flavonoid biosynthetic pathway of Deinococcus sp. 43 was constructed based on the genomic analysis and the detected flavonoids. In conclusion, this study represents the first comprehensive characterization of the flavonoid-producing pathway of Deinococcus. The findings demonstrate that the strain has excellent potential as a genetically engineered strain for the industrial production of flavonoids.

A review of different breast reconstruction methods.

Breast reconstruction is necessary for the comprehensive treatment of breast cancer. For successful breast reconstruction, the timing of surgery and the surgical methods used are vital. The methods of breast reconstruction can be divided into implant-based breast reconstruction (IBBR) and autologous breast reconstruction (ABR). With the development of acellular dermal matrix (ADM), IBBR has become more common in clinical practice. However, the choice for the position in which the implant should be placed (prepectoral or subpectoral) and the use of ADM is currently controversial. We summarized the differences in indications, complications, advantages, disadvantages, and prognosis between IBBR and ABR. We also compared the indications and complications of different flaps in ABR and found that the LD (latissimus dorsi) flap is suitable for Asian women who have a low body mass index (BMI) and a low incidence of obesity, while the DIEP (deep inferior epigastric perforator) flap can be used in patients with severe breast ptosis. In conclusion, immediate breast reconstruction with an implant or expander is the primary method, as it causes lesser scarring and requires a shorter time compared to ABR. However, for patients with severe breast ptosis or reluctant to receive an implant, ABR can be performed for a satisfying cosmetic result. Indications and complications of different flaps in ABR are also inconsistent. Surgeons should make surgical plans based on the preferences and conditions of each patient. In the future, breast reconstruction methods need to be further refined, and minimally invasive and personalized approaches need to be implemented to provide more benefits to patients.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Insertion sequence contributes to the evolution and environmental adaptation of Acidithiobacillus.

BACKGROUND: The genus Acidithiobacillus has been widely concerned due to its superior survival and oxidation ability in acid mine drainage (AMD). However, the contribution of insertion sequence (IS) to their biological evolution and environmental adaptation is very limited. ISs are the simplest kinds of mobile genetic elements (MGEs), capable of interrupting genes, operons, or regulating the expression of genes through transposition activity. ISs could be classified into different families with their own members, possessing different copies. RESULTS: In this study, the distribution and evolution of ISs, as well as the functions of the genes around ISs in 36 Acidithiobacillus genomes, were analyzed. The results showed that 248 members belonging to 23 IS families with a total of 10,652 copies were identified within the target genomes. The IS families and copy numbers among each species were significantly different, indicating that the IS distribution of Acidithiobacillus were not even. A. ferrooxidans had 166 IS members, which may develop more gene transposition strategies compared with other Acidithiobacillus spp. What's more, A. thiooxidans harbored the most IS copies, suggesting that their ISs were the most active and more likely to transpose. The ISs clustered in the phylogenetic tree approximately according to the family, which were mostly different from the evolutionary trends of their host genomes. Thus, it was suggested that the recent activity of ISs of Acidithiobacillus was not only determined by their genetic characteristics, but related with the environmental pressure. In addition, many ISs especially Tn3 and IS110 families were inserted around the regions whose functions were As/Hg/Cu/Co/Zn/Cd translocation and sulfur oxidation, implying that ISs could improve the adaptive capacities of Acidithiobacillus to the extremely acidic environment by enhancing their resistance to heavy metals and utilization of sulfur. CONCLUSIONS: This study provided the genomic evidence for the contribution of IS to evolution and adaptation of Acidithiobacillus, opening novel sights into the genome plasticity of those acidophiles.

The Potency of Serum Omentin-1 Quantification in Predicting Major Adverse Cardiac and Cerebrovascular Events Risk in Patients Receiving Hemodialysis.

Omentin-1 regulates inflammation, lipid accumulation, endothelial dysfunction, and atherosclerosis; the latter factors contribute to the occurrence of major adverse cardiac and cerebrovascular events (MACCE). This study aimed to explore the predictive implication of serum omentin-1 for MACCE risk in patients receiving hemodialysis. A total of 319 patients receiving hemodialysis and 160 healthy controls were prospectively enrolled in this study. Omentin-1 from serum was detected by enzyme-linked immunosorbent assay. MACCE was recorded during follow-up (median 18.9 months; range 1.9-62.9 months) in patients receiving hemodialysis. Omentin-1 was reduced in patients receiving hemodialysis versus healthy controls (P < 0.001). In patients receiving hemodialysis, omentin-1 was negatively related to C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol (all P < 0.05); whereas omentin-1 was not related to other clinical characteristics. Notably, the 1-year, 2-year, 3-year, 4-year, and 5-year accumulating MACCE rates in patients receiving hemodialysis were 7.9%, 18.3%, 25.9%, 36.1%, and 41.4%, respectively. Interestingly, high omentin-1 related to decreased accumulating MACCE rate (P = 0.003), which was further validated by multivariate Cox regression analysis (hazard ratio = 0.458, P = 0.006). Additionally, by direct comparison, omentin-1 was reduced in hemodialysis patients who experienced MACCE compared to those who did not (P < 0.001); meanwhile, the receiver operator characteristic curve displayed that omentin-1 had an acceptable ability to estimate MACCE risk with an area under the curve (95% confidence interval) of 0.703 (0.628-0.777). Serum omentin-1 reflects reduced inflammation and lipid accumulation, as well as predicts decreased MACCE risk in patients receiving hemodialysis.

Dynamic variation of Paris polyphylla root-associated microbiome assembly with planting years.

MAIN CONCLUSION: P. polyphylla selectively enriches beneficial microorganisms to help their growth. Paris polyphylla (P. polyphylla) is an important perennial plant for Chinese traditional medicine. Uncovering the interaction between P. polyphylla and the related microorganisms would help to utilize and cultivate P. polyphylla. However, studies focusing on P. polyphylla and related microbes are scarce, especially on the assembly mechanisms and dynamics of the P. polyphylla microbiome. High-throughput sequencing of the 16S rRNA genes was implemented to investigate the diversity, community assembly process and molecular ecological network of the bacterial communities in three root compartments (bulk soil, rhizosphere, and root endosphere) across three years. Our results demonstrated that the composition and assembly process of the microbial community in different compartments varied greatly and were strongly affected by planting years. Bacterial diversity was reduced from bulk soils to rhizosphere soils to root endosphere and varied over time. Microorganisms benefit to plants was selectively enriched in P. polyphylla roots as was its core microbiome, including Pseudomonas, Rhizobium, Steroidobacter, Sphingobium and Agrobacterium. The network's complexity and the proportion of stochasticity in the community assembly process increased. Besides, nitrogen metabolism, carbon metabolism, phosphonate and phosphinate metabolism genes in bulk soils increased over time. These findings suggest that P. polyphylla exerts a selective effect to enrich the beneficial microorganisms and proves the sequential increasing selection pressure with P. polyphylla growth. Our work adds to the understanding of the dynamic processes of plant-associated microbial community assembly, guides the selection and application timing of P. polyphylla-associated microbial inoculants and is vital for sustainable agriculture.

A Phase IIb, single arm, multicenter trial of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer who received at least two prior treatments.

Refractory or relapsing metastatic triple-negative breast cancer (mTNBC) has a poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate, targeting human trophoblast cell-surface antigen 2 (Trop-2). This is the first report of SG's efficacy and safety in Chinese patients with mTNBC. EVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in Chinese patients with mTNBC who failed ≥2 prior chemotherapy regimens. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the Independent Review Committee. Secondary endpoints included: duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and safety. Eighty female Chinese patients (median age 47.6 years; range 24-69.9 years) received ≥1 SG dose with a median of 8 treatment cycles by the cutoff date (August 6, 2021). Median number of prior systemic cancer treatments was 4.0 (range 2.0-8.0). ORR and CBR were reported 38.8% (95% confidence interval [CI]: 28.06-50.30) and 43.8% (95% CI, 32.68-55.30) of patients, respectively. The median PFS was 5.55 months (95% CI, 4.14-N/A). SG-related Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 71.3%, the most common were neutrophil count decreased (62.5%), white blood cell count decreased (48.8%) and anemia (21.3%); 6.3% discontinued SG because of TEAEs. SG demonstrated substantial clinical activity in heavily pretreated Chinese patients with mTNBC. The observed safety profile was generally manageable.

Estimation of appropriate dietary intake of iodine among lactating women in China based on iodine loss in breast milk.

OBJECTIVE: Data on iodine loss in breast milk, which are critical for establishing the appropriate dietary iodine intake for lactating women, is currently limited. A study was conducted to assess iodine loss in breast milk among Chinese lactating women to estimate the appropriate dietary intake of iodine. METHODS: A total of 54 pairs of healthy, lactating women and their infants aged 0-6 months were recruited from Tianjin and Luoyang cities in China. A 4 days infant weighing study was conducted to assess iodine loss in the breast milk of lactating women. Mothers were required to weigh and record their infants' body weights before and after each feeding for a 24 h period from 8:00 am to 8:00 am. During the weighing study, 2812 breast milk samples and 216 24-h urine samples were collected from each lactating mother for four consecutive days. In addition, a 3 days 24 h dietary record, including salt weighing and drinking water samples collecting, was performed by each lactating mother to determine dietary iodine intake during the weighing study. RESULTS: The average dietary iodine intake of lactating women was 323 ± 80 µg/d. The median breast milk iodine concentration and 24 h urinary iodine concentration of lactating women were 154 (122-181) and 135 (104-172) µg/L, respectively. The mean volume of breast milk and the mean iodine loss in the breast milk of lactating women were 711 ± 157 mL/d and 112 ± 47 µg/d, respectively. The appropriate dietary intake of iodine among lactating Chinese women is approximately 260 µg/d. CONCLUSIONS: Based on the iodine loss in breast milk (110 µg/d) found in this study, and the estimated average requirement of iodine for adults, the appropriate dietary intake of iodine among lactating Chinese women is 260 µg/d, which is higher than the 240 µg/d recommended by the China Nutrition Science Congress in 2013.

Predicting Intention to Participate in Community Physical Activities for Adults with Physical Disabilities.

Structural equation modeling was used to derive a relationship predicting the intention to participate in community physical activity among community-dwelling adults with a physical disability in Xiamen, China. The data were collected in a cross-sectional survey. The structural equation modeling combined biomedicine and the theory of planned behavior. It integrated ratings using the rehabilitation set from the international classification of functioning, disability, and health and role-physical scores from the short form 36 health survey questionnaire instrument. The model demonstrated a good ability to predict self-reported participation intentions, explaining 62% of the variance. The standard coefficients showed that activity limitation (27%), role-physical score (21%) and body impairment (14%) were the most influential predictors. ICF-RS ratings and role-physical ratings together can usefully predict physically disabled adults' intention of participating in community physical activities. Suggestions are presented for multidisciplinary intervention and improving this portion of the WHO's classification system.

The novel distribution of intracellular and extracellular flavonoids produced by Aspergillus sp. Gbtc 2, an endophytic fungus from Ginkgo biloba root.

Here, we reported a Ginkgo endophyte, Aspergillus sp. Gbtc 2, isolated from the root tissue. Its flavonoid biosynthesis pathway was reconstructed, the effect of phenylalanine on the production of flavonoids was explored, and the flavonoid metabolites were identified with the high-resolution Liquid chromatography-mass spectrometry (LC-MS). Some essential genes were annotated to form the upstream of the complete biosynthesis pathway, indicating that Aspergillus sp. Gbtc 2 has the ability to synthesize the C6-C3-C6 flavonoid monomers. HPLC results showed that adding an appropriate amount of phenylalanine could promote the production of flavonoids by Aspergillus Gbtc 2. LC-MS results depicted a significant difference in many flavonoids between intracellularly and extracellularly. Most of the flavonoids gathered in the cell contained glycosylation groups, while almost all components with multiple hydroxyls showed much higher concentrations extracellularly than intracellularly; they likely have different biological functions. A variety of these substances can be mapped back to the pathway pattern of flavonoid biosynthesis and prove the ability of flavonoid production once again. This study expanded the information on flavonoid biosynthesis in Aspergillus and provided a solid theoretical basis for developing the fungi into genetically engineered strains undertaking flavonoid industrialized production.

Development of an unsupervised cycle contrastive unpaired translation network for MRI-to-CT synthesis.

PURPOSE: The purpose of this work is to develop and evaluate a novel cycle-contrastive unpaired translation network (cycleCUT) for synthetic computed tomography (sCT) generation from T1-weighted magnetic resonance images (MRI). METHODS: The cycleCUT proposed in this work integrated the contrastive learning module from contrastive unpaired translation network (CUT) into the cycle-consistent generative adversarial network (cycleGAN) framework to effectively achieve unsupervised CT synthesis from MRI. The diagnostic MRI and radiotherapy planning CT images of 24 brain cancer patients were obtained and reshuffled to train the network. For comparison, the traditional cycleGAN and CUT were also implemented. The sCT images were then imported into a treatment planning system to verify their feasibility for radiotherapy planning. The mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM) between the sCT and the corresponding real CT images were calculated. Gamma analysis between sCT- and CT-based dose distributions was also conducted. RESULTS: Quantitative evaluation of an independent test set of six patients showed that the average MAE was 69.62 ± 5.68 Hounsfield Units (HU) for the proposed cycleCUT, significantly (p-value < 0.05) lower than that for cycleGAN (77.02 ± 6.00 HU) and CUT (78.05 ± 8.29). The average PSNR was 28.73 ± 0.46 decibels (dB) for cycleCUT, significantly larger than that for cycleGAN (27.96 ± 0.49 dB) and CUT (27.95 ± 0.69 dB). The average SSIM for cycleCUT (0.918 ± 0.012) was also significantly higher than that for cycleGAN (0.906 ± 0.012) and CUT (0.903 ± 0.015). Regarding gamma analysis, cycleCUT achieved the highest passing rate (97.95 ± 1.24% at the 2%/2 mm criteria and 10% dose threshold) but was not significantly different from the others. CONCLUSION: The proposed cycleCUT could be effectively trained using unaligned image data, and could generate better sCT images than cycleGAN and CUT in terms of HU number accuracy and fine structural details.

Aging-based molecular classification and score system in ccRCC uncovers distinct prognosis, tumor immunogenicity, and treatment sensitivity.

Objective: Aging is a complex biological process and a major risk factor for cancer development. This study was conducted to develop a novel aging-based molecular classification and score system in clear cell renal cell carcinoma (ccRCC). Methods: Integrative analysis of aging-associated genes was performed among ccRCC patients in the TCGA and E-MTAB-1980 cohorts. In accordance with the transcriptional expression matrix of 173 prognostic aging-associated genes, aging phenotypes were clustered with the consensus clustering approach. The agingScore was generated to quantify aging phenotypes with principal component analysis. Tumor-infiltrating immune cells and the cancer immunity cycle were quantified with the ssGSEA approach. Immunotherapy response was estimated through the TIDE algorithm, and a series of tumor immunogenicity indicators were computed. Drug sensitivity analysis was separately conducted based on the GDSC, CTRP, and PRISM analyses. Results: Three aging phenotypes were established for ccRCC, with diverse prognosis, clinical features, immune cell infiltration, tumor immunogenicity, immunotherapeutic response, and sensitivity to targeted drugs. The agingScore was developed, which enabled to reliably and independently predict ccRCC prognosis. Low agingScore patients presented more undesirable survival outcomes. Several small molecular compounds and three therapeutic targets, namely, CYP11A1, SAA1, and GRIK4, were determined for the low agingScore patients. Additionally, the high agingScore patients were more likely to respond to immunotherapy. Conclusion: Overall, our findings introduced an aging-based molecular classification and agingScore system into the risk stratification and treatment decision-making in ccRCC.

Feiyanning downregulating CXCLs/CXCR2 axis to suppress TANs infiltration in the prevention of lung cancer metastasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tumor-associated neutrophils (TANs) play an important role in tumor metastasis. The Traditional Chinese medicine (TCM) Feiyanning (FYN) has been clinically proven to effectively prevent the recurrence and metastasis of lung cancer, improve immunity, and prolong the survival period of lung cancer patients. However, its anti-metastatic immune mechanism has not been fully elucidated. To this end, we studied the mechanism of FYN's regulation of neutrophils infiltration in the tumor microenvironment (TME). AIM OF THE STUDY: To explore the anti-metastatic mechanism of FYN from the perspective of anti-immunosuppressive phenotype neutrophils infiltration in the TME. MATERIALS AND METHODS: TCM network pharmacological analysis was used to predict Feiyanning effective target. Flow cytometry was used to detect the proportion of immune cell subsets in the TME. Lung metastases were investigated in C57 mice by tail vein injection. Protein expression was evaluated by immunohistochemistry and Western blot. Gene expression was evaluated by qRT-PCR. RESULTS: FYN could reshape the tumor immune microenvironment. It prevents Tregs, M2 macrophages, and neutrophils infiltration, as well as recruits T cells, NK cells, and DCs, and improves DCs activation. In addition, FYN could regulate the polarization of TANs, inhibit the infiltration of neutrophils with an immunosuppressive phenotype, downregulate CXCLs/CXCR2 axis and inhibitory factors like Arg-1 and TGF-ß, and up-regulate the immune effector molecule ICAM-1. Furthermore, FYN increases anti-tumor immune effects in the TME to prevent tumor cells from spreading to the lungs. CONCLUSION: This study clarifies the potential mechanism of FYN in regulating neutrophils infiltration and anti-metastasis. FYN may regulate neutrophils infiltration in the TME by regulating CXCLs/CXCR2 axis.