miR-34b-3p-mediated regulation of STC2 and FN1 enhances chemosensitivity and inhibits proliferation in cervical cancer.

Dysregulation of microRNA (miRNA) expression in cancer is a significant factor contributing to the progression of chemoresistance. The objective of this study is to explore the underlying mechanisms by which miR-34b-3p regulates chemoresistance in cervical cancer (CC). Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues. In this study, we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin (DDP). Subsequently, miR-34b-3p mimics are transfected into SiHa/DDP cells. It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation, migration, and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death. Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2 and FN1 in SiHa/DDP cells, contrary to the expression pattern of miR-34b-3p. Moreover, STC2 and FN1 contribute to DDP resistance, proliferation, migration, invasion, and decreased apoptosis in CC cells. Through dual-luciferase assay analysis, we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC. Finally, rescue experiments demonstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance, proliferation, migration and invasion in CC cells. In conclusion, our findings support the role of miR-34b-3p as a tumor suppressor in CC. This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.

Chlorogenic acid ameliorates intestinal inflammation by inhibiting NF-κB and endoplasmic reticulum stress in lipopolysaccharide-challenged broilers.

Intestinal inflammation is a primary contributor to poor growth performance during poultry production. Chlorogenic acid (CGA) is a natural phenolic acid that exhibits superior anti-inflammatory activity and improved intestinal health. To investigate the protective effects and molecular mechanisms of CGA during intestinal inflammation in lipopolysaccharide (LPS)-challenged broilers, we randomly divided 288 one-day-old male Cobb broilers into 4 groups: a control group fed a basal diet (CON group), a basal diet + LPS group (LPS group), and 2 basal diet groups fed 500 or 750 mg/kg CGA + LPS (CGA_500 or CGA_750 groups). Broilers were injected with LPS or saline at 15, 17, 19, and 21 d old. Chlorogenic acid supplementation improved the growth performance of LPS-challenged broilers by increasing average daily gain (ADG) and reducing feed/gain (F/G) ratios (P < 0.05). CGA also improved intestinal barrier function in LPS-challenged boilers by enhancing jejunum morphology and integrity, decreasing intestinal permeability, and increasing occludin 3, zonula occludens-1, and mucin 2 expression (P < 0.05). CGA supplementation also improved systemic and jejunum antioxidant capacity by significantly enhancing glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities (P < 0.05), and reducing malonaldehyde (MDA) and protein carbonyl (PCO) levels (P < 0.05). Chlorogenic acid supplementation reduced systemic and jejunum pro-inflammatory cytokines (interleukin (IL)-1ß, IL-6, and IL-12) and increased anti-inflammatory cytokines (IL-10) in LPS-challenged broilers (P < 0.05) by inhibiting the toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway (P < 0.05). In addition, the protective effects of CGA toward intestinal inflammation and apoptosis appeared to be correlated with inhibited endoplasmic reticulum (ER) stress (P < 0.05). In summary, CGA supplementation improved intestinal morphology and integrity by inhibiting TLR4/NF-κB and ER stress pathways, which potentially reduced oxidative stress and inflammation, and ultimately improved the growth performance of LPS-challenged broilers.

Bacillus subtilis HW2 enhances growth performance and alleviates gut injury via attenuation of endoplasmic reticulum stress and regulation of gut microbiota in broilers under necrotic enteritis challenge.

This study investigated the effects of Bacillus subtilis HW2 on the growth performance, immune response, endoplasmic reticulum (ER) stress, and intestinal health in broilers with necrotic enteritis. Three hundred 1-day-old male Cobb 500 broilers (33.88 ± 2.34 g) were randomly allocated to 5 groups including non-infected control (NC group), basal diet + necrotic enteritis challenge (NE group), basal diet + 1 × 106 CFU/g B. subtilis HW2 + necrotic enteritis challenge (L-Pro group), basal diet + 5 × 106 CFU/g B. subtilis HW2 + necrotic enteritis challenge (M-Pro group), and basal diet + 1 × 107 CFU/g B. subtilis HW2 + necrotic enteritis challenge (H-Pro group), with 6 replicates per group. All broilers except NC group were orally given with sporulated coccidian oocysts at day 14 and Clostridium perfringens from days 19 to 21. Results showed that L-Pro and M-Pro groups improved growth performance and intestinal morphology in necrotic enteritis-challenged broilers, and L-Pro, M-Pro, and H-Pro groups improved intestinal barrier function and immune response and decreased ER stress in necrotic enteritis-challenged broilers. Analysis of the gut microbiota revealed that L-Pro group increased the abundances of Alistipes, Coprobacter, Barnesiella, and Limosilactobacillus, decreased Erysipelatoclostridium abundance on day 42 in necrotic enteritis-challenged broilers. M-Pro group increased Turicibacter abundance on day 28 and the abundances of Alistipes, Barnesiella, and Limosilactobacillus on day 42 in necrotic enteritis-challenged broilers. H-Pro group decreased Romboutsia abundance on day 28 and unidentified_Clostridia abundance on day 42 in necrotic enteritis-challenged broilers. Analysis of short-chain fatty acids (SCFAs) revealed higher isobutyric acid and isovaleric acid levels in L-Pro and M-Pro groups than NE group. Correlation analysis revealed the correlations between the biochemical parameters and gut microbiota as well as SCFAs, especially Romboutsia, Barnesiella, Coprobacter, isobutyric acid, and isovaleric acid. Overall, our results indicated that B. subtilis HW2 supplementation could ameliorate necrotic enteritis infection-induced gut injury. The optimal dietary supplementation dosage of Bacillus subtilis HW2 was 5 × 106 CFU/g.

Effectiveness of perioperative low-dose esketamine infusion for postoperative pain management in pediatric urological surgery: a prospective clinical trial.

BACKGROUND: Postoperative pain is common in pediatric urological surgery. The study assess the impact of perioperative intravenous infusion of low-dose esketamine on postoperative pain in pediatric urological surgery. METHODS: Pediatric patients (n = 80) undergoing urological surgery were randomized into four groups. Patients in the control group were administered an analgesic pump containing only hydromorphone at a dose of 0.1 mg/kg (Hydromorphone Group 1, H1) or 0.15 mg/kg (Hydromorphone Group 2, H2). Patients in the experimental group were injected intravenously with 0.3 mg/kg of esketamine (Esketamine group 1, ES1) or equal volume of saline (Esketamine Group 2, ES2) during anesthesia induction. Esketamine 1.0 mg/kg and hydromorphone 0.1 mg/kg were added to the analgesic pump. Face, Leg, Activity, Crying, and Comfort (FLACC) scale or the Numerical Rating Scale (NRS) and adverse effects were recorded at 2, 6, 24, and 48 h postoperatively. Additionally, total and effective PCA button presses were recorded. RESULTS: In comparison to the H1 group, the pain scores were notably reduced at all postoperative time points in both the ES1 and H2 groups. The ES2 group exhibited lower pain scores only at 24 and 48 h postoperatively. When compared to the H2 group, there were no significant differences in pain scores at various postoperative time points in the ES2 group. However, the ES1 group demonstrated significantly lower pain scores at 6, 24 and 48 h postoperatively, and these scores were also significantly lower than those observed in the ES2 group. The total and effective number of PCA button presses in the ES1, ES2 and H2 group were lower than that in the H1 group (P < 0.001). The incidence of adverse effects within 48 h after surgery was 15% in ES1, 22% in ES2, 58% in H1, and 42% in H2, respectively (P = 0.021). CONCLUSIONS: The use of low-dose esketamine infusion in analgesia pump can effectively alleviates postoperative pain in pediatric urological patients, leading to a significant reduction in the number of analgesic pump button press. The combined approach of perioperative anesthesia induction and analgesia pump administration is recommended for optimal pain management in these patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry- ChiCTR2300073879 (24/07/2023).

Incorporation of Decidual Stromal Cells Derived Exosomes in Sodium Alginate Hydrogel as an Innovative Therapeutic Strategy for Advancing Endometrial Regeneration and Reinstating Fertility.

Intrauterine adhesion (IUA) stands as a prevalent medical condition characterized by endometrial fibrosis and scar tissue formation within the uterine cavity, resulting in infertility and, in severe cases, recurrent miscarriages. Cell therapy, especially with stem cells, offers an alternative to surgery, but concerns about uncontrolled differentiation and tumorigenicity limit its use. Exosomes, more stable and immunogenicity-reduced than parent cells, have emerged as a promising avenue for IUA treatment. In this study, a novel approach has been proposed wherein exosomes originating from decidual stromal cells (DSCs) are encapsulated within sodium alginate hydrogel (SAH) scaffolds to repair endometrial damage and restore fertility in a mouse IUA model. Current results demonstrate that in situ injection of DSC-derived exosomes (DSC-exos)/SAH into the uterine cavity has the capability to induce uterine angiogenesis, initiate mesenchymal-to-epithelial transformation (MET), facilitate collagen fiber remodeling and dissolution, promote endometrial regeneration, enhance endometrial receptivity, and contribute to the recovery of fertility. RNA sequencing and advanced bioinformatics analysis reveal miRNA enrichment in exosomes, potentially supporting endometrial repair. This finding elucidates how DSC-exos/SAH mechanistically fosters collagen ablation, endometrium regeneration, and fertility recovery, holding the potential to introduce a novel IUA treatment and offering invaluable insights into the realm of regenerative medicine.

Chlorogenic acid protects against intestinal inflammation and injury by inactivating the mtDNA-cGAS-STING signaling pathway in broilers under necrotic enteritis challenge.

This study aimed to determine the effects of chlorogenic acid (CGA) on the growth performance, intestinal health, immune response, and mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in broilers under necrotic enteritis (NE) challenge. The 180 one-day-old male Cobb 500 broilers with similar body weight of 44.59 ± 1.39 g were randomly allocated into 3 groups. The groups were control diet (Control group), control diet + NE challenge (NE group), and control diet + 500 mg/kg CGA + NE challenge (NE + CGA group), with 6 replicates per treatment. All broilers except the Control group were given sporulated coccidian oocysts (d 14) and Clostridium perfringens (d 19-21) by oral gavage. Our findings showed that CGA improved the growth performance and intestinal morphology in broilers under NE challenge. CGA supplementation elevated the barrier function in broilers under NE challenge, which reflected in the decreased serum concentrations of D-lactate and diamine oxidase, and upregulated jejunal protein expression of occludin. CGA supplementation also improved the immune function, which reflected in the increased concentrations and gene expressions of anti-inflammatory factors, and decreased concentrations and gene expressions of proinflammatory factors. CGA supplementation further enhanced intestinal cell proliferation and differentiation, which manifested in the increased number of goblet cells and positive cells of proliferating cell nuclear antigen on d 28 and 42. Furthermore, CGA supplementation decreased the mtDNA (d 42) and mitochondrial reactive oxygen species levels (d 28 and 42), and increased the mitochondrial membrane potential (d 42) and mitochondrial complex I (d 28 and 42) or III (d 28) activity. Broilers challenged with NE had upregulated jejunal protein expressions of cGAS, phospho-TANK-binding kinase 1, and phospho-interferon regulatory factor 7 compared with the Control group, which were downregulated after CGA supplementation. In conclusion, dietary supplementation CGA could protect against intestinal inflammation and injury by reducing the leakage of mtDNA and inactivating the cGAS-STING signaling pathway in broilers under NE challenge.

MdDEWAX decreases plant drought resistance by regulating wax biosynthesis.

Apple epidermal wax protects plants from environmental stresses, determines fruit gloss and improves postharvest storage quality. However, the molecular mechanisms underlying the biosynthesis and regulation of apple epidermal waxes are not fully understood. In this study, we isolated a MdDEWAX gene from apple, which localized in the nucleus, expressed mainly in apple fruit, and induced by drought. We transformed the MdDEWAX gene into Arabidopsis, and found that heterologous expression of MdDEWAX reduced the accumulation of cuticular waxes in leaves and stems, increased epidermal permeability, the rate of water loss, and the rate of chlorophyll extraction of leaves and stems, altered the sensitivity to ABA, and reduced drought tolerance. Meanwhile, overexpression or silencing of the gene in the epidermis of apple fruits decreased or increased wax content, respectively. This study provides candidate genes for breeding apple cultivars and rootstocks with better drought tolerance.

Effects of Lactobacillus plantarum HW1 on Growth Performance, Intestinal Immune Response, Barrier Function, and Cecal Microflora of Broilers with Necrotic Enteritis.

The purpose of the study was to investigate the effects of Lactobacillus plantarum HW1 on growth performance, intestinal immune response, barrier function, and cecal microflora of broilers with necrotic enteritis. In total, 180 one-day-old male Cobb 500 broilers were randomly allocated into three groups comprising a non-infected control (NC) group, basal diet + necrotic enteritis challenge (NE) group, and basal diet + 4 × 106 CFU/g Lactobacillus plantarum HW1 + necrotic enteritis challenge (HW1) group. Broilers in the NE and HW1 groups were orally given sporulated coccidian oocysts at day 14 and Clostridium perfringens from days 19 to 21. The results showed that the HW1 treatment increased (p < 0.05) the average daily gain of broilers from days 15 to 28 and from days 0 to 28 compared with the NE group. Moreover, the HW1 treatment decreased (p < 0.05) the oocysts per gram of excreta, intestinal lesion scores, ileal interleukin (IL) 1ß and tumor necrosis factor α levels, and serum D-lactic acid and diamine oxidase levels, while increasing (p < 0.05) the ileal IL-10 level, thymus index, and protein expressions of ileal occludin and ZO-1. Additionally, the HW1 treatment decreased (p < 0.05) the jejunal and ileal villus height, jejunal villus height/crypt depth value, and cecal harmful bacterial counts (Clostridium perfringens, Salmonella, Escherichia coli, and Staphylococcus aureus), and increased (p < 0.05) the cecal Lactobacillus count. In conclusion, dietary supplementation with 4 × 106 CFU/g Lactobacillus plantarum HW1 could relieve necrotic enteritis infection-induced intestinal injury and improve growth performance in broilers by improving intestinal barrier function and regulating intestinal microbiology.

Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial.

CDK4/6 inhibitors have shown a synergistic effect with anti-HER2 therapy in hormone receptor (HR)-positive and HER2-positive breast cancer (BC). In this phase 2 study (NCT04293276), we aim to evaluate a dual-oral regimen of CDK4/6 inhibitor dalpiciclib combined with HER2 tyrosine kinase inhibitor pyrotinib as front-line treatment in women with HER2-positive advanced BC (n = 41) including those with HR-negative disease. The primary endpoint is the objective response rate, and secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety. With a median follow-up of 25.9 months, 70% (28/40) of assessable patients have a confirmed objective response, meeting the primary endpoint. The median PFS is 11.0 months (95% CI = 7.3-19.3), and OS data are not mature. The most common grade 3 or 4 treatment-related adverse events (AEs) are decreased white blood cell count (68.3%), decreased neutrophil count (65.9%), and diarrhea (22.0%). Most AEs are manageable, and no treatment-related deaths occur. These findings suggest that this combination may have promising activity and manageable toxicity. Further investigation is needed.

Acute bilateral multiple subcortical infarcts as manifestation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterised by recurrent subcortical ischemic events, migraine with aura, dementia and mood disturbance. Strokes are typically lacunar infarcts; however, bilateral multiple subcortical lacunar infarcts have been described only sporadically. METHOD: We described four CADASIL patients who presented with acute bilateral multiple subcortical infarcts as the first manifestation. We also briefly summarised the case reports detailing the bilateral multiple infarcts in CADASIL. RESULTS: Patient 1 and patient 2 were family members, and they presented with cognitive impairment. Patient 3 and patient 4 presented with slurred speech and hemiparesis. Patients 1, 3 and 4 developed hemodynamic fluctuations before the occurrence of ischemic stroke. Laboratory tests revealed elevated fibrinogen levels in patients 3 and 4. The brain magnetic resonance imaging showed acute bilateral multiple subcortical infarcts on the periventricular white matter in all the patients. CONCLUSION: CADASIL, with a poor brain hemodynamic reserve, is vulnerable to hemodynamic alterations (e.g. blood pressure fluctuation, dehydration, blood loss and anaemia) and intolerable to ischemia and hypoxia of the brain. Furthermore, blood hypercoagulation may contribute to acute multiple bilateral infarctions in CADASIL. Therefore, it is necessary to avert these predispositions in CADASIL patients in their daily life.

Risk of esketamine anesthesia on the emergence delirium in preschool children after minor surgery: a prospective observational clinical study.

Emergence delirium (ED) is a common mental complication during recovery from anesthesia. However, studies on the effects of esketamine, an intravenous anesthetic for pediatrics, on ED are still lacking. This study aimed to investigate the effects of a single-dose of esketamine during anesthesia induction on ED after minor surgery in preschool children. A total of 230 children (aged 2-7 years) completed the study. The exposed group (0.46 mg kg-1: average dose of esketamine) was associated with an increased incidence of ED and a higher maximum Pediatric Anesthesia Emergence Delirium score than the non-exposed group. The length of post-anesthesia care unit stay was longer in the exposed group than the non-exposed group. In contrast, extubation time, face, legs, activity, cry, and consolability (FLACC) scores, and the proportions of rescue analgesics were comparable between the two groups. Furthermore, five factors, including preoperative anxiety scores, sevoflurane and propofol compared with sevoflurane alone for anesthesia maintenance, dezocine for postoperative analgesia, FLACC scores, and esketamine exposure, were associated with ED. In conclusion, a near-anesthetic single-dose of esketamine for anesthesia induction may increase the incidence of ED in preschool children after minor surgery. The use of esketamine in preschool children for minor surgery should be noticed during clinical practice.

Clinicopathological features and prognosis of breast cancer combined with symptomatic bone marrow metastases: A 10-year, single-center, real-world study of 67 cases.

PURPOSE: Bone marrow metastasis (BMM) is uncommon in breast cancer (BC), and early diagnosis is challenging. BMM lacks definitive treatment options and poses a great threat to the survival of patients. Herein, we investigated the clinical features, prognosis, and factors affecting the prognosis of BC patients with symptomatic BMM to help improve the understanding of this disease and provide effective diagnostic and treatment strategies. METHODS: Clinical data of 67 patients with BC and BMM were retrospectively analyzed for clinical characteristics, treatment, and prognosis of BMM. Univariate and multivariate analyses were performed to determine factors affecting overall survival following BMM (BMMOS). RESULTS: Among patients with BMM, 86.6% were diagnosed after bone metastasis (BM), while 13.4% were diagnosed simultaneously with BM. A total of 73.1%, 13.4%, and 13.4% of the patients had hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) tumors, HER2+ tumors, and triple-negative tumors, respectively. The most common symptoms of BMM were the coexistence of anemia and thrombocytopenia (26.9%), anemia (19.4%), and pancytopenia (17.9%). The median BMMOS was 7.6 months (95% CI, 3.9-11.3). Univariate and multivariate analyses showed that BMMOS was associated with platelet count <75 × 109 /L at the time of BMM diagnosis. The BMMOS of patients who underwent endocrine therapy, combined chemotherapy, and mono-chemotherapy after BMM was 15.7, 9.7, and 8.6 months, respectively, whereas that of untreated patients was 2.9 months, and the difference among the results was statistically significant (χ2  = 20.102, p < 0.0001). Changes in patient hemogram and/or body temperature during treatment were consistent with the overall effect of the disease (p < 0.0001). CONCLUSION: BMM should be considered in BC patients with BM, an unexplained reduction in hemogram parameters, especially anemia and thrombocytopenia, and/or fever without chills. Active, effective, individualized treatment strategies can prolong BMMOS.

Microflows in two-generation alveolar cells at an acinar bifurcation.

The alveolus is a basic functional unit of the human respiratory system, and the airflow in the alveoli plays an important role in determining the transport and deposition of particulate matter, which is crucial for inhaled disease diagnosis and drug delivery. In the present study, taking advantage of the precise control ability of the microfluidic technique, a rhythmically expanding alveolar chip with multiple alveoli in two generations is designed and both the geometric and kinematic similarities are matched with the real human respiration system. With the help of a micro-PIV measurement system, the microflow patterns inside each alveolus can be studied. The observed vortex and radial flow patterns and the discovery of stagnant saddle points are similar to those captured in our previous platform with only one alveolus [Lv et al., Lab Chip 20, 2394-2402 (2020)]. However, the interactions between multiple alveoli also uncover new phenomena, such as the finding of stagnant saddle points in non-vortex flow patterns and significant differences in the flow pattern around the points between the time of T/4 and 3T/4. The obtained results could enrich the understanding of microflow in a whole alveolar tree with multiple generations.

MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis.

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels.

Diagnostic diversity and heterogeneity of tumors: a real-world study of metastasis re-biopsy in advanced breast cancer.

BACKGROUND: Re-biopsy of metastasis in advanced breast cancer (ABC) has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity. This study aimed to detect diagnostic diversity and inconsistencies among estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression levels between primary and metastatic lesions. METHODS: We conducted a retrospective analysis of 1670 cases of ABC patients who had undergone at least one lesion re-biopsy from January 2010 to December 2018. The pathological diagnosis of biopsies, distribution of biopsy sites, and severe puncture complications at each site were collected. In addition, the inconsistency rates and related factors of ER, PR, and HER2 expression between primary and metastatic lesions were analyzed fully considering patients' demographic profiles and disease characteristics. RESULTS: In total, 1670 cases of breast cancer (BC) patients diagnosed by pathology underwent one to four biopsies of recurrences or metastases in different sites or at different stages during the rescue treatment, producing 2019 histopathological specimens which were analyzed in the study. Pathological diagnosis showed that eight patients had benign pathological diagnoses, 11 patients had second primary malignant tumors but without recurrences of breast cancer, and 17 patients had pathologically confirmed breast cancer recurrences combined with second primary cancer. In 1173 patients who presented ER, PR, and HER2 expressions in primary and metastatic lesions, the inconsistency rates of ER, PR, and HER2 were 17.5% (205/1173), 31.3% (367/1173), and 13.9% (163/1173), respectively. The multivariate analysis showed that the age at the onset of breast cancer or adjuvant endocrine therapy was an independent factor affecting changes in PR expression level. Except one liver puncture with local hemorrhage and two lung punctures with hemopneumothorax, no other severe puncture complications occurred in 1950 non-surgical rebiopsies. CONCLUSIONS: The pathological diagnosis of metastasis re-biopsy of ABC was diverse, and the ER, PR, and HER2 expression levels were inconsistent between primary and metastatic lesions. Therefore, more attention should be paid to perform biopsies of relapsed and metastatic breast cancers routinely in clinical practice.

Ultrasound-guided quadratus lumborum block provided more effective analgesia for children undergoing lower abdominal laparoscopic surgery: a randomized clinical trial.

BACKGROUND: Postoperative pain treatment for pediatrics is often inadequate and the evidence of pediatric postoperative analgesia is scarce. To our knowledge, no report regarding the comparison among caudal block, transversus abdominis plane (TAP) block and quadratus lumborum (QL) block for children undergoing lower abdominal laparoscopic surgery was found at present. Thus this trial aimed to compare the efficacies of them for children undergoing lower abdominal laparoscopic surgery. METHODS: One hundred and eighty children aged from 1 to 12 years undergoing lower abdominal laparoscopic surgery were included and randomized to receive caudal block, TAP block or QL block. The primary outcome was the Face, Legs, Activity, Cry, and Consolability (FLACC) score at 30 min, 1 h, 4 h, 8 h, 12 h, and 24 h and tramadol consumption during first 24 h postoperatively. Secondary outcomes included the number of children received tramadol, time to first tramadol request, parents' satisfaction and postoperative adverse reactions. RESULTS: The QLB group had lower postoperative FLACC scores at 8 h (median difference - 0.43, P = 0.03) than the Caudal group and at 4 h (median difference - 0.6, P = 0.001) and 8 h (median difference - 0.43, P = 0.03) than the TAPB group. The tramadol consumption was lower in the QLB group (28.43 ± 6.55) than the TAPB group (37.17 ± 6.12, P = 0.023). Although the number of children received tramadol did not differ among the three groups, the time to first tramadol request was longer in the QLB group (7.20 ± 0.79) than the caudal group (8.42 ± 0.61, P = 0.008). No statistical difference was observed concerning other secondary outcomes. CONCLUSIONS: QLB produced more effective postoperative analgesia for children undergoing laparoscopic abdominal surgery compared with the TAPB and caudal block.

Microparticle Transport and Sedimentation in a Rhythmically Expanding Alveolar Chip.

Understanding the mechanism of particle transport and sedimentation in pulmonary alveolus is important for deciphering the causes of respiratory diseases and helping the development of drug delivery. In this study, taking advantage of the microfluidic technique, an experimental platform was developed to study particle behavior in a rhythmically expanding alveolar chip for a sufficient number of cycles. The alveolar flow patterns at different generations were measured for two cases with the gravity direction parallel or vertical to the alveolar duct. Affected by both the vortex flow inside the alveoli and the shear flow in the duct simultaneously, it was observed that particles inside the alveoli either escaped from the inlet of the alveolar duct or stayed in the alveoli, revealing the irreversibility of particle transport in the alveoli. At the earlier acinar generations, particles were inclined to deposit on the distal alveolar wall. The settling rates of particles of different sizes in the alveoli were also compared. This study provides valuable data for understanding particle transport and sedimentation in the alveoli.

Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial.

BACKGROUND: Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases. METHODS: We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051. FINDINGS: Between Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15·7 months (IQR 9·7-19·0). The intracranial objective response rate was 74·6% (95% CI 61·6-85·0; 44 of 59 patients) in cohort A and 42·1% (20·3-66·5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial. FUNDING: National Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Distress Thermometer in breast cancer: systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to reach a summarised estimate of distress prevalence screened by Distress Thermometer (DT) among patients with breast cancer and compare different pooled prevalence estimated between different subgroups. METHODS: Two independent interviewers conducted a systematic search from PubMed, EMBASE, Ovid and Cochrane Library and checked related reviews and meta-analyses for eligible studies. The studies that identified distress of patients with breast cancer with DT were included. After extracting demographic characteristics and distress prevalence, the pooled analysis and the forest plot were completed by using STATA V.12.0 software. We conducted a subgroup analysis based on demographic and methodological characteristics of the studies. The publication bias was estimated by funnel plot. RESULTS: Seventeen studies describing 3870 patients with breast cancer were included in this meta-analysis. The distress prevalence of patients with breast cancer varied from 25.3% to 71.7% among these studies. The pooled distress prevalence was 50% (95% CI 49% to 52%) for the overall sample. The pooled distress prevalence rates in DT ≥7, DT ≥5 and DT ≥4 subgroups were 37% (95% CI 35% to 40%), 45% (95% CI 40% to 49%) and 62% (95% CI 60% to 65%), respectively. The distress prevalence had statistically significant differences between subgroups, which were differentiated by the initial time of distress identified, papers' publication time, patients' average age and country. There was no publication bias among the included studies. CONCLUSION: The distress prevalence was high among patients with breast cancer. Routine and timely screening of distress for patients with breast cancer is of great significance in oncology management.