Prevention of breast cancer-related lymphoedema: Quality of clinical practice guidelines and variations in recommendations.

AIM: We aimed to evaluate the quality of clinical practice guidelines (CPGs) for breast cancer related lymphoedema (BCRL) and compare the similarities and differences in recommendations. BACKGROUND: Many CPGs of BCRL have been developed; however, their recommendations and quality are controversial. METHODS: Relevant papers were retrieved from electronic databases, professional associations and guideline development organizations, from 1 January 2015 to 30 September 2021. The Appraisal of Guidelines Research and Evaluation (AGREE) II instrument was used to evaluate the quality of the guidelines. Intraclass correlation coefficient (ICC) analysis was used to evaluate the overall consistency among evaluators. RESULTS: Eight CPGs were included. The ICC values evaluation for CPGs ranged from 0.76 to 0.95, with good consensus among evaluators. The highest median score was 68.75% (61.46, 72.22%) for clarity, and the lowest was 37.50% (25.78, 51.30%) for applicability. The NICE, ACS/ACSO and APTA CPGs were rated well in most areas. Professional health education, individualized exercise programme and regular surveillance are the main methods to prevent lymphoedema. CONCLUSION: In the past 6 years, the quality of BCRL guidelines has varied greatly, especially in the domains of rigour and applicability. Interrater agreement was excellent, but recommendation showed some inconsistencies in the details.

Dexmedetomidine for prevention of propofol injection pain upon induction of anesthesia: a meta-analysis.

PURPOSE: Propofol injection pain is a very common problem during the induction of general anesthesia. The purpose of this review is to evaluate the effectiveness of dexmedetomidine for the prevention of propofol injection pain so as to provide evidence for future clinical applications. METHODS: PubMed, Embase, Cochrane library, and Google Scholar databases were searched for relevant randomized controlled trials examining the use of dexmedetomidine for the prevention of propofol injection pain. The pooled risk ratio (RR) with corresponding 95% confidence intervals (CI) was calculated employing fixed-effects or random-effects models, depending upon the heterogeneity of the included trials. Because of the wide variety of interventions investigated, three comparisons of studies were established, dexmedetomidine compared with saline, lidocaine, and ketamine. RESULTS: Compared with saline, dexmedetomidine allowed more patients to experience no pain upon propofol injection (RR = 0.26, 95% CI (0.18, 0.38), P < 0.00001). Dexmedetomidine at doses of < 1 µg/kg did not show superiority in relieving propofol injecting pain compared with lidocaine (RR = 1.28, 95% CI (0.82, 2.00), P = 0.04). Dexmedetomidine is less effective than ketamine in reducing pain on propofol injection with a statistically significant P value of < 0.000010 (RR = 1.93, 95% CI (1.51, 2.47)). The report of adverse effects is rare, dexmedetomidine is a safe method to reduce propofol injection pain. CONCLUSION: Pretreatment with dexmedetomidine may be a useful alternative for reducing pain on propofol injection, even though dexmedetomidine is less effective than lidocaine and ketamine.

[Genetic analysis and treatment for an infant with cerebral creatine deficiency syndrome type 2].

OBJECTIVE: To carry out genetic and metabolite analysis for an infant with cerebral creatine deficiency syndrome type 2 (CCDS2). METHODS: Clinical data of the child was collected. Whole-exome sequencing was carried out to identify potential variants by next generation sequencing. Candidate variants were confirmed by Sanger sequencing. Metabolites were determined by tandem mass spectrometry and magnetic resonance spectroscopy. Treatment was carried out following the diagnosis and genetic counseling for the affected family. RESULTS: Two novel heterozygous variants (c.289delC and c.392-1G>C) of the GAMT gene were identified in the proband, which were respectively inherited from her father and mother. In silico analysis suggested both variants to be pathogenic. Creatine (Cr) level of the child was very low, and cerebral guanidinoacetate (GAA) level was slightly increased. But both had recovered to normal in two weeks, and cerebral Cr level was significantly improved after two months. Intellectual and motor development of the child were significantly improved. CONCLUSION: The child was diagnosed with CCDS type 2, for which pathogenic variants of the GAMT gene may be accountable. Treatment has attained a satisfactory effect for the patient.

[Clinical features and SLC6A8 gene mutations of cerebral creatine deficiency syndrome I: an analysis of two families].

This article reports the clinical and genetic features of two cases of cerebral creatine deficiency syndrome I (CCDSI) caused by SLC6A8 gene mutations. Both children were boys. Boy 1 (aged 2 years and 10 months) and Boy 2 (aged 8 years and 11 months) had the clinical manifestations of delayed mental and motor development, and convulsion. Their older brothers had the same symptoms. The mother of the boy 1 had mild intellectual disability. The genetic analysis showed two novel homozygous mutations, c.200G>A(p.Gly67Asp) and c.626_627delCT(p.Pro209Argfs*87), in the SLC6A8 gene on the X chromosome, both of which came from their mothers. These two novel mutations were rated as possible pathogenic mutations and were not reported in the literature before. This study expands the mutation spectrum of the SLC6A8 gene and has great significance in the diagnosis of boys with delayed development, and epilepsy.

Coupling-based Huygens' meta-atom utilizing bilayer complementary plasmonic structure for light manipulation.

Huygens' meta-atom is the basic building unit of Huygens' metasurfaces allowing for almost arbitrary wavefront shaping across a surface. We here present a kind of Huygens' meta-atom by coupling a nanodisk to its Babinet-complementary structure (nanohole), and develop an optical lumped nanocircuit model to analyze vertical and lateral coupling effects and resonance frequencies. Simulation results show that the tuned coupling via lateral misalignment between the two nanostructures is sufficient to shape the wavefront without changing the dimensions or orientations of antennas. By tuning the coupling via lateral misalignment, we design a reflective gradient metasurface based on one coupled mode and a high-efficiency transmissive gradient metasurface working in the spectral overlap of electric and magnetic resonances to realize beam deflection. The proposed coupling-based Huygens' meta-atom is a new building block for plasmonic metasurfaces with enhanced light-matter interactions, high-efficiency and almost arbitrary wavefront shaping over the full electromagnetic spectrum.

Simultaneous di-oxygenation and denitrification in an internal circulation baffled bioreactor.

An internal circulation baffled bioreactor was employed to realize simultaneous di-oxygenation of phthalic acid (PA) and denitrification of nitrate, which require aerobic and anoxic conditions, respectively. Adding a small concentration of succinate as an exogenous electron donor stimulated PA di-oxygenation, which produced readily oxidizable downstream products whose oxidation also enhanced denitrification of nitrate; succinate addition also stimulated denitrification. Depending on the concentration of PA, addition of 0.17 mM succinate increased the PA removal rate by 25 and 42%, while the corresponding nitrate removal rate was increased by 73 and 51%. UV/H2O2 advanced oxidation of PA had the same effects as adding succinate, since succinate is generated by UV/H2O2; this acceleration effect was approximately equivalent to adding 0.17 mM succinate.

Sodium selenite suppresses hepatitis B virus transcription and replication in human hepatoma cell lines.

Hepatitis B virus (HBV) infection is one of the most serious and prevalent health problems worldwide. Current anti-HBV medications have a number of drawbacks, such as adverse effects and drug resistance; thus, novel potential anti-HBV reagents are needed. Selenium (Se) has been shown to be involved in both human immunodeficiency virus and hepatitis C virus infections, but its role in HBV infection remains unclear. To address this, sodium selenite (Na2SeO3 ) was applied to three HBV cell models: HepG2.2.15 cells, and HuH-7 cells transfected with either 1.1 or 1.3× HBV plasmids. Cytotoxicity of Na2SeO3 was examined by Cell Counting Kit-8. Levels of viral antigen expression, transcripts, and encapsidated viral DNA were measured by enzyme-linked immunosorbent assay, northern blot, and Southern blot, respectively. There was no obvious cytotoxicity in either HepG2.2.15 or HuH-7 cells with <2.5 µM Na2SeO3 . Below this concentration, Na2SeO3 suppressed HBsAg and HBeAg production, HBV transcript level, and amount of genomic DNA in all three tested models, and suppression level was enhanced in line with increases in Na2 SeO3 concentration or treatment time. Moreover, the inhibitory effect of Na2SeO3 on HBV replication can be further enhanced by combined treatment with lamivudine, entecavir, or adefovir. Thus, the present study clearly proves that Na2SeO3 suppresses HBV protein expression, transcription, and genome replication in hepatoma cell models in a dose- and time-dependent manner.

Synergistic effect of ozonation and ionizing radiation for PVA decomposition.

Ozonation and ionizing radiation are both advanced oxidation processes (AOPs) without chemical addition and secondary pollution. Also, the two processes' efficiency is determined by different pH conditions, which creates more possibilities for their combination. Importantly, the combined process of ozonation and ionizing radiation could be suitable for treating wastewaters with extreme pH values, i.e., textile wastewater. To find synergistic effects, the combined process of ozonation and ionizing radiation mineralization was investigated for degradation of polyvinyl alcohol (PVA) at different pH levels. A synergistic effect was found at initial pH in the range 3.0-9.4. When the initial pH was 3.0, the combined process of ozonation and ionizing radiation gave a PVA mineralization degree of 17%. This was 2.7 times the sum achieved by the two individual processes, and factors of 2.1 and 1.7 were achieved at initial pH of 7.0 and 9.4, respectively. The combined process of ozonation and ionizing radiation was demonstrated to be a feasible strategy for treatment of PVA-containing wastewater.

CRTC2 enhances HBV transcription and replication by inducing PGC1α expression.

BACKGROUND: Hepatitis B virus (HBV) transcription and replication are essentially restricted to hepatocytes. Based on the HBV enhancer and promoter complex that links hepatic glucose metabolism to its transcription and replication, HBV adopts a regulatory system that is unique to the hepatic gluconeogenic genes. CRTC2, the CREB-regulated transcription coactivator 2, is a critical switch modulating the gluconeogenic program in response to both hormonal and intracellular signals. However, the relationship between CRTC2 and HBV transcription and replication remains unclear. METHODS: To analyze the influence of CRTC2 on HBV transcription and replication, CRTC2 expression construct or siRNA was cotransfected with plasmids containing enhancer II/core promoter complex-controlled luciferase or 1.3× wtHBV genome in Huh-7 cells. Luciferase activity, HBV core protein expression, HBV transcripts, and DNA replication intermediates were measured by luciferase assays, western blots, real-time polymerase chain reaction (PCR), and Southern blots, respectively. Forskolin (FSK) or phosphorylation-defective CRTC2 mutants were further utilized to elucidate the potential mechanism. siRNA against peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) was also used to examine the mediator involved in CRTC2-regulated HBV biosynthesis in Huh-7 cells. RESULTS: CRTC2 overexpression increased HBV transcription and replication in Huh-7 cells, including levels of core protein expression, mRNA, and DNA replication intermediates. Correspondingly, CRTC2 knock down by siRNA reduced HBV biosynthesis. FSK treatment strongly enhanced the effect of CRTC2 through triggering the dephosphorylation and nuclear entry of CRTC2. The phosphorylation-defective mutant (S171A/S275A) of CRTC2 localized in the nucleus and was constitutively active, which dramatically promoted HBV transcription and replication similar to FSK-treated wild-type CRTC2. Knock down of PGC1α, whose expression was induced by CRTC2, greatly compromised the enhancing effect of CRTC2 on HBV transcription and replication. CONCLUSIONS: Our results clearly indicate that non-phosphorylated CRTC2 strongly enhances HBV biosynthesis through inducing PGC1α expression. Further study of the mechanisms will elucidate the importance of metabolic signals on HBV transcription and replication, and offer insight into potential targets for developing anti-HBV agents.

Sex differences in symptom network structure of depression, anxiety, and self-efficacy among people with diabetes: a network analysis.

Aims: The present study aims to explore the relations between symptoms of depression and anxiety and self-efficacy among people with diabetes. At the same time, we also examined the sex difference between network structures. Methods: This study recruited 413 participants with diabetes, and they completed Generalized Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire (PHQ-9), and the Self-efficacy for Diabetes (SED). Symptom network analysis and network comparison test were used to construct and compare the depression-anxiety symptom network models of the female and male groups. Finally, we conducted flow diagrams to explore the symptoms directly or indirectly related to self-efficacy. Results: The strongest edges in the depression-anxiety symptom networks are the edge between "GAD3" (Excessive worry) and "GAD4" (Trouble relaxing) and the edge between "PHQ1" (Anhedonia) and "PHQ4" (Energy) in the female and male groups, respectively. Most of the symptoms with the highest EI and bridge EI are related to worry and nervousness. Additionally, in the flow diagram of the female group, "PHQ6" (Guilt) has a high negative association with self-efficacy. Conclusion: Females with diabetes are more vulnerable to depression and anxiety. Interventions targeting key symptoms in the network may be helpful in relieving the psychological problems among people with diabetes.

Autologous Platelet-Rich Gel Accelerates Diabetic Wound Healing Through Inhibition of Ferritinophagy.

Aims: The objective was to examine the efficacy of autologous platelet-rich gel (APG) in treating diabetic wound and investigate the association between APG and ferritinophagy. Methods: A total of 32 patients with diabetic foot (DF) and Wagner grade 1 to 2 were included. Within the APG group, individuals with DF received weekly APG treatment. In the non-APG group, DF patients received daily dressing changes. Flow cytometry quantified the proportion of endothelial progenitor cells (EPCs) in peripheral blood on days 0 and 10. The diabetic rat model was induced using Streptozotocin. Two circular skin wounds were created on the backs of rats. The normal glucose group received daily dressing changes on the wound. In the diabetic group, the left wound underwent daily dressing changes, whereas the right wound was treated with APG once a week. CD34 levels were tested 7 days after the skin damage. The levels of glutathione peroxidase 4 (GPX4), Nuclear Receptor Coactivator 4 (NCOA4), Light chain 3 (LC3), and Masson staining were quantified on 14 days. The wound area and wound healing rate were separately measured at 0 and 14 days after the injury, regardless of DF patients or diabetic rats. Results: The wound healing rate was higher in the APG group than in the non-APG group, regardless of DF patients or diabetic rats. The APG group had a greater ΔEPCs% in DF patients than the non-APG group. Regarding rat experiment, the APG group exhibited lower levels of NCOA4, and LC3 expressions and a shorter wound healing time. However, the APG group showed higher levels of CD34 expression, GPX4 protein, and collagen fibers than the non-APG group. Conclusions: Autologous platelet-rich gel accelerated the wound healing rate in diabetic populations and rats. Autologous platelet-rich gel promoted EPCs counts, collagen fiber volume, and vessel numbers. Autologous platelet-rich gel decreased LC3 and NCOA4 expression, but increased GPX4 protein expression. The possible mechanism was the inhibition of ferritinophagy.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Soluble forms of PD-1 and sPD-L1/2 in serum and urine of patients with head and neck cancer and their clinical significance.

This study explored the soluble forms of PD-1 and sPD-L1/2 in serum and urine of patients with head and neck cancer (HNCs) and associated the data with clinical state and 5-year survival. The sPD-1 and sPD-L1/2 levels were evaluated by ELISA in sufferers (N=110) and normal controls (N=82). Patients in the case group were more likely to be male smokers or former smokers. Compared with the normal control group, the serum levels of sPD-1, sPD-L1 and sPD-L2 and the urine level of sPD-L1 in patients with HNCs were increased. Furthermore, sPD-1 and sPD-L1 serum levels existed a positive connection, and sPD-1 and sPD-L2 serum levels positively correlated in HNCs sufferers. The urine sPD-1 and sPD-L1 had a positive relationship. sPD-1 serum levels had a positive connection with urine sPD-1, sPD-L1 urine levels had a positive relationship with sPD-L1, and sPD-L2 serum levels positively connected to urine sPD-L2. Lower serum sPD-1 and sPD-L1/L2 were associated with disease progression and survival at the examination time. sPD-1 and sPD-L1/L2 serum levels above median were markedly related to a decreased probability of 5-years OS in patients with HNCs. The sPD-1 and sPD-L1/2 were complementary markers representing clinical condition and illness outcomes for HNCs patients. The sPD-L1 might accelerate the characterization of high-risk patients with disapproving illness outcomes. sPD-1 and sPD-L1/2 could be easily accessed through liquid biopsy. The incorporation of them as indicators for risk evaluation throughout treatment scheduling and follow-up seems to be an appreciated method.

Fourteen cases of cerebral creatine deficiency syndrome in children: a cohort study in China.

Background: This study sought to analyze the clinical characteristics, biochemical metabolic indications, treatment results, and genetic spectrum of cerebral creatine deficiency syndrome (CCDS), estimate the prevalence of CCDS in Chinese children and provide a reference to guide clinical practice. Methods: We performed a retrospective cohort study of 3,568 children with developmental delay at Children's Hospital of Fudan University over a 6-year period (January 2017-December 2022). Metabolites in the blood/urine were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and genetic testing was performed by next-generation sequencing (NGS). The patients with suspected CCDS were ultimately diagnosed by magnetic resonance spectroscopy (MRS). The patients were then treated and followed up. All the reported cases of CCDS, their gene mutations, and treatment results in China were summarized. Results: Ultimately, 14 patients were diagnosed with CCDS. The age of onset was between 1-2 years. All the patients had developmental delay, 9 had epilepsy, and 8 had movement or behavioral disorders. A total of 17 genetic variants were identified, including 6 novel variants. c.403G>A, c.491dupG of the guanidinoacetate methyltransferase (GAMT) gene had a relatively high frequency. After treatment, patients with GAMT deficiency showed obvious improvements, and brain creatine (Cr) levels recovered to 50-80% of normal, 1 patient achieved normal neurodevelopment, and 3 patients became epilepsy free; however, 6 male patients with X-linked creatine transporter gene (SLC6A8) variants received Cr for 3-6 months with no effect, and 2 patients received combined therapy with few improvements. Conclusions: The prevalence of CCDS is ~0.39% in Chinese children with developmental delay. A low-protein diet, Cr and, ornithine were useful for patients with GAMT deficiency. Male patients with SLC6A8 deficiency showed only limited improvement on combined therapy.

Age-related reference intervals for serum phytosterols in children by gas chromatography-mass spectrometry and its application in diagnosing sitosterolemia.

BACKGROUND AND AIMS: Serum phytosterol profiles are essential for the diagnosis and management of sitosterolemia. However, pediatric reference interval (RI) studies are scarce and various mass spectrometry (MS) approaches for phytosterol analysis still face multiple limitations. Therefore, an optimized gas chromatography (GC)-MS assay and age-related RIs in children are both required. MATERIALS AND METHODS: Cholesterol and phytosterols (sitosterol, campesterol, cholestanol, stigmasterol, and sitostanol) were simultaneously determined by optimized GC-MS and performance was verified by the lower limit of quantification (LLOQ), linearity, precision, recovery, matrix effects, and method comparison. Healthy children (247 males and 263 females) were recruited, sex and age dependence were assessed using quantile regression (2.5th percentile and 97.5th percentile), and RIs were established according to Clinical and Laboratory Standards Association guideline C28-A3. These RIs were validated in 19 patients with sitosterolemia and 23 patients with hypercholesterolemia. RESULTS: The optimized method shortened the sample processing time by approximately 60 min. Among the five phytosterols, all precision, recoveries (ranging from 89.97% to 104.94%), and relative matrix effects (%CV: ranging from 0.08% to 13.88%) met the specifications. GC-MS showed good agreement with lower cholesterol concentrations compared to conventional enzymatic methods. No significant differences between males and females were observed for all phytosterols, but age dependency was found and age-related RIs were established accordingly. Five phytosterols were significantly higher than RIs in patients with sitosterolemia. CONCLUSION: We established age-related RIs for five phytosterols in children based on an optimized GC-MS assay, providing a screening tool for the diagnosis of sitosterolemia in children.

Hydrogen sulfide decreases the levels of ROS by inhibiting mitochondrial complex IV and increasing SOD activities in cardiomyocytes under ischemia/reperfusion.

Inhibition of oxidative stress has been reported to be involved in the cardioprotective effects of hydrogen sulfide (H(2)S) during ischemia/reperfusion (I/R). However, the mechanism whereby H(2)S regulates the level of cardiac reactive oxygen species (ROS) during I/R remains unclear. Therefore, we investigated the effects of H(2)S on pathways that generate and scavenge ROS. Our results show that pretreating rat neonatal cardiomyocytes with NaHS, a H(2)S donor, reduced the levels of ROS during the hypoxia/reoxygenation (H/R) condition. We found that H(2)S inhibited mitochondrial complex IV activity and increased the activities of superoxide dismutases (SODs), including Mn-SOD and CuZn-SOD. Further studies indicated that H(2)S up-regulated the expression of Mn-SOD but not CuZn-SOD. Using a cell-free system, we showed that H(2)S activates CuZn-SOD. An isothermal titration calorimetry (ITC) analysis indicated that H(2)S directly interacts with CuZn-SOD. Taken together, H(2)S inhibits mitochondrial complex IV and activates SOD to decrease the levels of ROS in cardiomyocytes during I/R.

Inhibition of DNAJC12 Inhibited Tumorigenesis of Rectal Cancer via Downregulating HSPA4 Expression.

Background: Dysregulation of DnaJ heat shock protein family (HSP40) member C12 (DNAJC12) is implicated in the malignancy progression of multiple cancers. The current study aimed to determine the biology function and mechanism of DNAJC12 in rectal cancer (RC). Methods: RC tissues, adjacent tissues, RC cell lines, and normal colorectal epithelial cell lines were collected to analyze DNAJC12 expression. The abilities of DNAJC12 on proliferation, migration, and apoptosis of RC cells were detected by CCK-8, wound healing, and flow cytometry assays. Co-IP assays were carried out to confirm the association between DNAJC12 and HSPA4. The effect of DNAJC12 on tumor growth was detected by using the xenograft model of nude mice. Results: Elevation of DNAJC12 was uncovered in RC tissues and cell lines. DNAJC12 upregulation facilitated RC cell proliferation and migration and induced apoptosis, while DNAJC12 interference showed the opposite results. Besides, HSAP4 served as a potential binding protein for DNAJC12. Rescue experiments revealed that elevated of HSAP4 restored the impact of DNAJC12 silencing on the cell functions. Finally, DNAJC12 silencing hampered tumor growth of RC in vivo. Conclusion: In summary, this study highlighted a key player of DNAJC12 in modulating the malignant biological progression of RC via DNAJC12/HSPA4 axis, displaying a potential therapeutic target for RC.

Autoimmune Polyendocrinopathy Induced by an Antibody (KN046) That Simultaneously Inhibits PD-L1 and CTLA-4: A Case Report and Literature Review.

Endocrine adverse reactions are one of the most common adverse reactions in the treatment of immune checkpoint inhibitors (ICIs), mainly involving the pituitary gland, pancreas, thyroid gland, adrenal gland and other glands, resulting in corresponding endocrine dysfunction. We report a 45-year-old man with non-small-cell lung cancer who developed hypophysitis 11 months after initiation of treatment with an anti-PD-L1/CTLA-4 bispecific antibody (KN046) that blocks both programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), followed by regular oral replacement doses of prednisone and levothyroxine tablets. The patient was diagnosed with type 1 diabetes mellitus (T1DM) with diabetic ketoacidosis (DKA) 25 months after the start of immunotherapy, presenting with acute hyperglycemic symptoms, ketoacidosis, and negative diabetic autoantibodies. By describing a case of KN046 immunotherapy involving multiple endocrine glands and reviewing relevant literature, we were able to summarize the clinical characteristics of KN046 immunotherapy-induced endocrine system-related immune-related adverse events (irAEs) for use in early detection, diagnosis and treatment.

Efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy regimen in Chinese patients with HER2-positive early breast cancer: a real-world retrospective multi-center cohort study.

Background: Pertuzumab plus trastuzumab combined with chemotherapy has become a standard neoadjuvant therapy option for patients with high-risk human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). There is still not enough evidence for the efficacy and safety of neoadjuvant pertuzumab and trastuzumab plus chemotherapy in HER2-positive BC patients in China, both in clinical trials and real-world settings. This study aimed to assess the efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive BC in real-world clinical application. Methods: We retrospectively collected the data from the electronic medical records of HER2-positive patients treated with neoadjuvant trastuzumab and pertuzumab plus chemotherapy from December 2018 to May 2021 at 21 hospitals located in Hunan Province, China, including age, American Joint Committee on Cancer (AJCC) stage, clinical tumor size, clinical lymph node status, pathological characteristics (before neoadjuvant systemic therapy), treatment approach, adverse events to neoadjuvant therapy, and achievement of pathological complete response (pCR). The primary endpoint was the total rate of pCR, and the secondary endpoints were the rate of pCR of each subgroup and the safety of dual anti-HER2 therapy. Results: A total of 188 patients met the inclusion criteria and were included in the analysis. Of the 188 patients, 119 (63.3%) were diagnosed at stage II and 64 (34.0%) at stage III; 163 (86.7%) were cT2-3; 149 patients (79.3%) were ≥ cN1; 84 patients (44.7%) were hormone receptor (HR)-positive. pCR was observed in 88 of 188 patients (46.8%). The pCR rate of HR-negative patients (54.8%) was higher (P=0.014) than that of HR-positive patients (36.9%). Patients with Ki-67 <15% achieved a higher (P=0.033) pCR rate (68.2%) than those with Ki-67 ≥15% (44.0%). Anemia was the most common adverse event (63.4%), and the most common grade 3-4 adverse event was nausea and vomiting (8.5%). Conclusions: Our study confirmed the benefit of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy on pCR with a tolerable safety profile in routine clinical practice in Chinese patients with HER2-positive BC. HR-negativity and Ki-67 <15% were associated with pCR in these patients.

Ubiquitin-Fold Modifier-1 Participates in the Diabetic Inflammatory Response by Regulating NF-κB p65 Nuclear Translocation and the Ubiquitination and Degradation of IκBα.

BACKGROUND: Ubiquitin-fold modifier-1 (Ufm1) is a recently identified ubiquitin-like protein. We previously confirmed that Ufm1 expression was increased in diabetic mice. However, its role in the development of diabetes remains undefined. METHODS: Lentivirus-mediated gene knockdown and overexpression techniques were used to observe the effect of Ufm1 on the expression of inflammatory factors, adhesion molecules and chemokines, as well as the transcriptional activity of nuclear factor kappa-B (NF-κB) in macrophages. Western blot and immunofluorescence analyses were used to analyse the mechanism by which Ufm1 affects the transcriptional activity of NF-κB. Finally, the effects of Ufm1 on inflammation and pancreatic, renal and myocardial damage were observed in db/db mice. RESULTS: Knockdown of Ufm1 by lentivirus shRNA targeting Ufm1 (Lv-shUfm1) led to decreased secretion of IL-6, IL-1ß, ICAM-1, VCAM-1, MCP-1 and CXCL2 in RAW264.7 cells that were exposed to LPS and TNF-α, while lentiviral overexpression of Ufm1 (Lv-Ufm1) caused the opposite effect. Interestingly, further investigation indicated that Ufm1 induced NF-κB p65 nuclear translocation in RAW264.7 cells via increasing the ubiquitination and degradation of IκBα. In an in vivo experiment, pretreatment of db/db mice with Lv-shUfm1 reduced the mRNA levels of TNF-α, IL-6, IL-1ß, ICAM-1, VCAM-1, MCP-1 and CXCL2 in resident peritoneal macrophages (RPMs) and decreased the plasma levels of TNF-α, IL-6, IL-1ß, ICAM-1, VCAM-1, MCP-1 and CXCL2. Additionally, in Lv-Ufm1-treated mice, the inverse results were observed. Following treatment with Lv-shUfm1 and Lv-Ufm1, NF-κB p65 nuclear translocation in RPMs was decreased and increased, respectively. Importantly, we observed that Lv-shUfm1 injection led to a decrease in plasma glycaemia, a reduction in urinary albuminuria and cardiomyocyte hypertrophy and an improvement in the histopathological appearance of pancreatic, kidney and myocardial tissue. Pretreatment of the mice with Lv-shUfm1 inhibited macrophage infiltration in the pancreas, kidney and myocardial tissue. CONCLUSION: Our data elucidate a new biological function of Ufm1 that mediates inflammatory responses. Ufm1-mediated p65 nuclear translocation occurs by modulating the ubiquitination and degradation of IκBα. Moreover, downregulating Ufm1 is an effective strategy to prevent the development of type 2 diabetes and its complications.