The emerging predictive and prognostic role of HER2 in HER2-negative early breast cancer: a retrospective study.

PURPOSE: Many patients with early breast cancer (eBC) undergoing neoadjuvant chemotherapy do not achieve pathological complete response (pCR), which is a prognostic factor. We examined the role of HER2-low expression in predicting pCR and prognosis in HER2-negative eBC. METHODS: We evaluated patients with stage I-III HER2-negative BC, treated between 2013 and 2023 at The Royal Marsden NHS Foundation Trust, London. Tumors were classified based on estrogen receptor (ER) status and into HER2-low and HER2-zero subgroups. We analyzed pCR rates, relapse-free survival (RFS) and overall survival (OS). RESULTS: 754 patients were included in the analysis. pCR rate was 8.9% in the ER+ /HER2-low, 16.5% in the ER+ /HER2-zero, 38.9% in the ER- ER-/HER2-low and 35.9% in the ER-/HER2-zero eBC (p < 0.001). Multivariable analysis showed a significantly lower pCR rate in HER2-low compared to HER2-zero BC in the ER+ subgroup. At a median follow-up of 63.8 months (59.9-67.4), we observed longer OS in HER2-low compared to HER2-zero patients in the overall and in the ER+ population. There was no predictive or prognostic impact of HER2-low status in the ER- population. CONCLUSION: This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

Self-supporting noncovalent Choline Alginate/Tannic acid/Ag antibacterial films for strawberry preservation.

Packaging materials with peculiar antibacterial properties can shield off and inhibit microorganism proliferation, thus achieving packaging goals such as fresh-keeping, good hygiene, and biosafety. Especially, antibacterial films made of biocompatible substances have received wide attentions, which could effectively extend the shelf life, enhance food security, and guarantee economic benefits. Herein, a self-supporting hybrid antibacterial film was prepared based on non-covalently linked choline hydroxide (ChOH) and alginic acid (HAlg). Then tannic acid (TA) and silver ions were added to improve the mechanical and antimicrobial properties of this hybrid film. The rich hydroxyl groups from TA not only form multiple hydrogen bonds with ChAlg, but can also in situ reduce silver ions to silver nanoparticles, which were confirmed with various characterizations. In addition, the quantitative antibacterial test proved that the antibacterial rate was significantly improved after adding silver ions, reaching >60 %. In an actual storage test, we found that choline cation (Ch+) captured in antibacterial film by electrostatic interaction could achieve sustained release, i.e. sustainable bacteriostasis, and keep strawberries fresh for 48 h at room temperature. This work offers a new strategy for preparing antibacterial films via non-covalent weak interactions, explored an alternative antibacterial film for food packaging applications.

Cushing's Syndrome in Pregnancy Secondary to Adrenocortical Adenoma: A Case Series and Review.

PURPOSE: To present a case series of Cushing's syndrome (CS) during pregnancy caused by adrenocortical adenomas, highlighting clinical features, hormonal assessments and outcomes. METHODS: We describe five pregnant women with CS, detailing clinical presentations and laboratory findings. RESULTS: Common clinical features included a full moon face, buffalo back and severe hypertension. Elevated blood cortisol levels with circadian rhythm disruption and suppressed adrenocorticotrophic hormone (ACTH) levels were observed. Imaging revealed unilateral adrenal tumours. Two cases underwent laparoscopic adrenalectomies during the second trimester, while three had postpartum surgery. All required hormone replacement therapy, with postoperative pathological confirmation of adrenocortical adenomas. CONCLUSION: Diagnosis of CS during pregnancy is challenging due to overlapping features with normal pregnancy: elevated blood cortisol levels and abnormal diurnal rhythm of blood cortisol, suppressed aid diagnosis. Treatment should be individualised due to a lack of explicit optimum therapeutic approaches. Laparoscopic adrenalectomy may be an optimal choice, along with multidisciplinary management including hormone replacement therapy.

Etomidate enhances cerebellar CF-PC synaptic plasticity through CB1 receptor/PKA cascade in vitro in mice.

Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca2+ with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD.

A multiple Kirkendall strategy for converting nanosized zero-valent iron to highly active Fenton-like catalyst for organics degradation.

Nanosized zero-valent iron (nZVI) is a promising persulfate (PS) activator, however, its structurally dense oxide shell seriously inhibited electrons transfer for O-O bond cleavage of PS. Herein, we introduced sulfidation and phosphorus-doped biochar for breaking the pristine oxide shell with formation of FeS and FePO4-containing mixed shell. In this case, the faster diffusion rate of iron atoms compared to shell components triggered multiple Kirkendall effects, causing inward fluxion of vacancies with further coalescing into radial nanocracks. Exemplified by trichloroethylene (TCE) removal, such a unique "lemon-slice-like" nanocrack structure favored fast outward transfer of electrons and ferrous ions across the mixed shell to PS activation for high-efficient generation and utilization of reactive species, as evidenced by effective dechlorination (90.6%) and mineralization (85.4%) of TCE. [Formula: see text] contributed most to TCE decomposition, moreover, the SnZVI@PBC gradually became electron-deficient and thus extracted electrons from TCE with achieving nonradical-based degradation. Compared to nZVI/PS process, the SnZVI@PBC/PS system could significantly reduce catalyst dosage (87.5%) and PS amount (68.8%) to achieve nearly complete TCE degradation, and was anti-interference, stable, and pH-universal. This study advanced mechanistic understandings of multiple Kirkendall effects-triggered nanocrack formation on nZVI with corresponding rational design of Fenton-like catalysts for organics degradation.

Integrated analysis of multi-omics data reveals T cell exhaustion in sepsis.

Background: Sepsis is a heterogeneous disease, therefore the single-gene-based biomarker is not sufficient to fully understand the disease. Higher-level biomarkers need to be explored to identify important pathways related to sepsis and evaluate their clinical significance. Methods: Gene Set Enrichment Analysis (GSEA) was used to analyze the sepsis transcriptome to obtain the pathway-level expression. Limma was used to identify differentially expressed pathways. Tumor IMmune Estimation Resource (TIMER) was applied to estimate immune cell abundance. The Spearman correlation coefficient was used to find the relationships between pathways and immune cell abundance. Methylation and single-cell transcriptome data were also employed to identify important pathway genes. Log-rank test was performed to test the prognostic significance of pathways for patient survival probability. DSigDB was used to mine candidate drugs based on pathways. PyMol was used for 3-D structure visualization. LigPlot was used to plot the 2-D pose view for receptor-ligand interaction. Results: Eighty-four KEGG pathways were differentially expressed in sepsis patients compared to healthy controls. Of those, 10 pathways were associated with 28-day survival. Some pathways were significantly correlated with immune cell abundance and five pathways could be used to distinguish between systemic inflammatory response syndrome (SIRS), bacterial sepsis, and viral sepsis with Area Under the Curve (AUC) above 0.80. Seven related drugs were screened using survival-related pathways. Conclusion: Sepsis-related pathways can be utilized for disease subtyping, diagnosis, prognosis, and drug screening.

Age-related enhanced degeneration of bioprosthetic valves due to leaflet calcification, tissue crosslinking, and structural changes.

AIMS: Bioprosthetic heart valves (BHVs), made from glutaraldehyde-fixed heterograft materials, are subject to more rapid structural valve degeneration (SVD) in paediatric and young adult patients. Differences in blood biochemistries and propensity for disease accelerate SVD in these patients, which results in multiple re-operations with compounding risks. The goal of this study is to investigate the mechanisms of BHV biomaterial degeneration and present models for studying SVD in young patients and juvenile animal models. METHODS AND RESULTS: We studied SVD in clinical BHV explants from paediatric and young adult patients, juvenile sheep implantation model, rat subcutaneous implants, and an ex vivo serum incubation model. BHV biomaterials were analysed for calcification, collagen microstructure (alignment and crimp), and crosslinking density. Serum markers of calcification and tissue crosslinking were compared between young and adult subjects. We demonstrated that immature subjects were more susceptible to calcification, microstructural changes, and advanced glycation end products formation. In vivo and ex vivo studies comparing immature and mature subjects mirrored SVD in clinical observations. The interaction between host serum and BHV biomaterials leads to significant structural and biochemical changes which impact their functions. CONCLUSIONS: There is an increased risk for accelerated SVD in younger subjects, both experimental animals and patients. Increased calcification, altered collagen microstructure with loss of alignment and increased crimp periods, and increased crosslinking are three main characteristics in BHV explants from young subjects leading to SVD. Together, our studies establish a basis for assessing the increased susceptibility of BHV biomaterials to accelerated SVD in young patients.

Adult intussusception: a challenge to laparoscopic surgery?

Background: Intussusception can occur at any age and is common in children but less common in adults. This study aimed to evaluate our experience of 51 adult intussusception and study the etiology, clinical manifestations, diagnosis, and treatment. Methods: This analysis assessed the clinical manifestations, etiology, diagnosis, and treatment of adult intussusception in 51 adult patients at the Department of Gastrointestinal Surgery of China-Japan Union Hospital of Jilin University from January 2010 to December 2020. Results: The mean age of the cohort was 54.43 ± 18.21 years, and 42 patients were diagnosed by abdominal ultrasonography and abdominal computed tomography (CT). Among them, 76.5% (39/51) had abdominal pain, 11.8% (6/51) had blood in stool, and 5.9% (3/51) had a palpable abdominal mass. Of these, 62.7% had tumors: malignant accounted for 39.2% (20/51) and benign accounted for 23.5% (12/51). CT is the preferred imaging method with a sensitivity of 92.2%, while colonoscopy provides a complementary diagnosis in patients involving the colon. All patients underwent surgical treatment, including 21.6% (11/51) laparoscopic surgery, 74.5% (38/51) open surgery, and 5.9% (3/51) intussusception reduction during the operation. The average operation time of the open group was 133.27 ± 43.75 min and the average hospital stay was 16.24 ± 12.55 days, while the average operation time of the laparoscopic group was 140.50 ± 46.15 mins, and the average hospital stay was 16.60 ± 16.98 days (P > 0.05). Conclusion: Adult intussusception is a rare disease in clinic. Laparoscopic surgery can be useful and safe for adult intussusception.

Homeobox C4 promotes hepatocellular carcinoma progression by the transactivation of Snail.

Homeobox C4 (HOXC4) belongs to the homeoprotein family of transcription factors, which play a critical role in morphogenesis and differentiation during embryonic development. Aberrant expression of HOXC4 has been reported in several types of cancers. However, the role of HOXC4 in hepatocellular carcinoma (HCC) remains unknown. Here, we reported that HOXC4 is upregulated in HCC tissues and predicts a poor outcome in patients with HCC. HOXC4 promotes HCC progression and induces an EMT-like phenotype both in vitro and in vivo. Furthermore, we demonstrated that the EMT-related transcription factor Snail is a transcriptional target of HOXC4 and HOXC4 regulates EMT by regulation of transforming growth factor ß (TGF-ß) signaling in HCC. Together, our study suggests that HOXC4 as a novel potential therapeutic target for HCC therapy.

Studies of nanoparticle delivery with in vitro bio-engineered microtissues.

A variety of engineered nanoparticles, including lipid nanoparticles, polymer nanoparticles, gold nanoparticles, and biomimetic nanoparticles, have been studied as delivery vehicles for biomedical applications. When assessing the efficacy of a nanoparticle-based delivery system, in vitro testing with a model delivery system is crucial because it allows for real-time, in situ quantitative transport analysis, which is often difficult with in vivo animal models. The advent of tissue engineering has offered methods to create experimental models that can closely mimic the 3D microenvironment in the human body. This review paper overviews the types of nanoparticle vehicles, their application areas, and the design strategies to improve delivery efficiency, followed by the uses of engineered microtissues and methods of analysis. In particular, this review highlights studies on multicellular spheroids and other 3D tissue engineering approaches for cancer drug development. The use of bio-engineered tissues can potentially provide low-cost, high-throughput, and quantitative experimental platforms for the development of nanoparticle-based delivery systems.

Carbonized zeolitic imidazolate framework-67/polypyrrole: A magnetic-dielectric interface for enhanced microwave absorption properties.

Due to the high electromagnetic interference (EMI) pollution, electromagnetic wave (EMW) absorption materials have risen as an important research area in material science and technology. Herein, the prepared carbonized ZIF-67 (CZIF) nanocomposites with polypyrrole (PPy) showed significantly enhanced electromagnetic wave absorption performance. The CZIF-PPy nanocomposites were prepared by the solvothermal and in-situ polymerization method. The CZIF-PPy nanocomposites possess a decent reflection loss (RL) value between the 2-18 GHz frequency range. The enhanced surface properties and magnetic-dielectric interfacial polarization plays an important role to achieve higher reflection loss and broader absorption bandwidth. This work explains the importance of magnetic-dielectric interface and may lead to design of more advanced hybrid electromagnetic wave absorption systems.

Importance of Robust and Reliable Nanochannel Sealing for Enhancing Drug Delivery Efficacy of Hollow Mesoporous Nanocontainer.

Hollow mesoporous silica nanoparticles (HMSNPs) have been widely explored in the biomedical field as drug delivery nanocarriers by virtue of their large hollow cavity. However, the connectivity between the internal cavity and the outside environment by numerous nanochannels on the mesoporous shell allows for possible drug leakage, leading to nonsufficient drug loading due to unreliable capping of the nanopores. In addition, the issue of ensuring effective utilization of the hollow cavity for achieving high drug loading capacity of HMSNPs is seldom addressed. Thus, in this work, HMSNPs with the diameter of about 400 nm were prepared and completely encapsulated by growing an ultrathin nanolayer of aluminum oxide (Al2O3) of about 20 nm on the surface of the mesoporous shell with template-assisted sol-gel chemistry. The robust sealing layer of Al2O3 can ensure "zero release" of the delivery system under neutral conditions, which is crucial for achieving high drug loading capacity by physical encapsulation of cargo molecules within the hollow cavity. The Al2O3-coated HMSNP (denoted as HMSNP Al2O3 can improve the drug loading capacity up to about 35 wt %, realizing loading efficiency as high as ten times the maximum value without Al2O3 under the same conditions. Besides, the encapsulation nanolayer of Al2O3 would be degraded under the acidic condition to realize pH-responsive controlled release of the cargo molecules. We further carried out in vitro drug delivery experiments by using human epithelial cervix adenocarcinoma (HeLa) cells as the model and revealed much higher drug delivery efficacy within cancer cells compared to free doxorubicin (Dox) and Dox loaded HMSNP without sealing (HMSNP@Dox). The current work not only clarifies the importance of the surface encapsulation of the nanochannels when using HMSNPs as nanocarriers, but also provides a strategy to prepare fully encapsulated core-shell structures, which holds great potential for physically encapsulating various theranostic reagents in the biomedical field.

Intestinal Schwannoma: A Clinicopathological, Immunohistochemical, and Prognostic Study of 9 Cases.

BACKGROUND: Intestinal schwannoma is a type of intestinal interstitial tumor with a very low incidence. At present, there are few studies on intestinal schwannoma. METHODS: From January 2010 to January 2018, the patients diagnosed with intestinal schwannoma at the China-Japan Union Hospital of Jilin University were retrospectively reviewed. The patients' clinicopathological features and prognosis were analyzed. RESULTS: This study enrolled 9 patients with intestinal schwannoma, including 3 males and 6 females. The main symptoms of the patients were abdominal pain and melena. Abdominal computed tomography showed intussusception, slightly high-density shadowing in the intestine, thickening of the intestinal wall, and an intestinal mass. Colonoscopy and endoscopic ultrasonography showed submucosal masses without ulcer formation. Two patients underwent endoscopic biopsy, and the pathological results revealed inflammation and necrosis. One patient had increased neuron-specific enolase (NSE) levels. Immunohistochemical analysis showed that the tumor cells were positive for S-100 and negative for CD117, DOG-1, desmin, and smooth muscle actin. An average of 17 lymph nodes were found around the intestines in 4 patients, all of which demonstrated reactive hyperplasia. No recurrence or metastasis occurred during postoperative follow-up. CONCLUSIONS: Intestinal schwannoma is a rare tumor, and in our study its incidence was higher in women than in men. The main symptoms were abdominal pain and melena. Preoperative increases in NSE levels might contribute to a diagnosis. Complete surgical resection with free negative margins is the standard treatment for benign schwannoma. There was no recurrence or metastasis after complete surgical resection, suggesting that follow-up may not be required.

Gastrointestinal hemorrhage caused by adult intussusception secondary to small intestinal tumors: Two case reports.

RATIONALE: Adult intussusception is rarely observed, and the clinical manifestations are very atypical. The most common symptom is abdominal pain, while the incidence of hematochezia is relatively low. We report two cases of adult intussusception secondary to small intestinal tumors with gastrointestinal hemorrhage as the main symptom. PATIENT CONCERNS: Two men aged 19 and 54 years were successively referred to our department due to intermittent hematochezia. The hemoglobin levels of the two patients declined progressively, and conservative treatment was ineffective. DIAGNOSES: The first patient underwent an abdominal computed tomography angiography examination, which showed that the intestine and its mesentery were tortuous, suggesting an intra-abdominal hernia or intussusception. The second patient underwent an abdominal computed tomography examination, which suggested a high possibility of an intussusception. The two patients were diagnosed as adult intussusception caused by small intestinal tumors. INTERVENTIONS: Emergency laparoscopic explorations were performed. Enteroenteric intussusceptions caused by ileal tumors were found during surgery. Reduction of the intussusceptions and resection of the ileal tumors were performed. OUTCOMES: The patients recovered well after surgery, and postoperative pathology showed that the tumors were a vascular hamartoma polyp and a lipoma. LESSONS: Adult intussusception is very rare, particularly with gastrointestinal hemorrhage as the main symptom. Isolated hamartoma polyp is a rare cause of intussusception in adults. The clinical manifestations of adult intussusception are very atypical, and thus, making a preoperative diagnosis is difficult. Abdominal CT or CTA is an effective diagnostic method for adult intussusception. For adult patients with gastrointestinal hemorrhage caused by intussusceptions, active surgery should be performed when conservative treatment is not effective. Laparoscopic surgery is a safe and effective treatment for adult intussusceptions caused by benign diseases.

Hepatic portal venous gas associated with colon cancer: A case report and literature review.

RATIONALE: Hepatic portal venous gas (HPVG) is a very rare radiological finding that occurs when gas enters the portal venous system. HGVG can be caused by various diseases, with the most common being intestinal ischemia or necrosis. While there are few reports of HPVG associated with colon cancer, we report a case of HPVG associated with advanced colon cancer. DIAGNOSIS: The diagnosis of this patient was HPVG caused by colon cancer. INTERVENTIONS: Left colon cancer resection, pancreatic tail resection, splenectomy, and transverse colostomy were performed. OUTCOMES: The patient recovered well, and postoperative paraffin pathology confirmed that the resected tumor was colon cancer. LESSONS: Abdominal computed tomography is an effective method for diagnosing and monitoring HPVG. Klebsiella pneumonia is a potential gas-producing microorganism associated with HPVG, which may be confirmed by Blood culture or drainage culture. The prognosis of HPVG is closely related to the underlying pathology. Surgery should be performed early when there are signs of intestinal ischemia, necrosis, or perforation.

Structural basis for the immunomodulatory function of cysteine protease inhibitor from human roundworm Ascaris lumbricoides.

Immunosuppression associated with infections of nematode parasites has been documented. Cysteine protease inhibitor (CPI) released by the nematode parasites is identified as one of the major modulators of host immune response. In this report, we demonstrated that the recombinant CPI protein of Ascaris lumbricoides (Al-CPI) strongly inhibited the activities of cathepsin L, C, S, and showed weaker effect to cathepsin B. Crystal structure of Al-CPI was determined to 2.1 Å resolution. Two segments of Al-CPI, loop 1 and loop 2, were proposed as the key structure motifs responsible for Al-CPI binding with proteases and its inhibitory activity. Mutations at loop 1 and loop 2 abrogated the protease inhibition activity to various extents. These results provide the molecular insight into the interaction between the nematode parasite and its host and will facilitate the development of anthelmintic agents or design of anti-autoimmune disease drugs.

Nspc1 regulates the key pluripotent Oct4-Nanog-Sox2 axis in P19 embryonal carcinoma cells via directly activating Oct4.

Nspc1 is an identified transcription repressor. However, transiently up-regulated or down-regulated Nspc1 in P19 embryonal carcinoma cells affects expression levels of Oct4, Sox2 and Nanog in a positive correlation. Luciferase activity assays verified that Nspc1 regulates the Oct4 promoter in a dose dependent manner. ChIP assay shows that Nspc1 activates Oct4 by directly binding to the (-1021 to -784) region of Oct4 promoter. Dominant negative analysis indicated the activation is dependent on the retinoid acid response element (RARE). We demonstrated Nspc1 has a positive role in maintaining the pluripotency of P19 cells by directly regulating Oct4.

[Progress on cell infiltration in electrospun scaffold].

OBJECTIVE: To introduce the research progress on the technique of improving cell infiltration in electrospun scaffold. METHODS: The recent original articles about improving cell infiltration in electrospun scaffold were extensively reviewed and analyzed. RESULTS: The technique includes regulation of the electrospun parameters, modification of electrospun scaffold, and dynamic culture of scaffold-cells composite etc. The effect is limited and most of them need further optimization. CONCLUSION: Cell infiltration in electrospun scaffold is of great significance in tissue engineering application. The relatively high compressed density and small pore size have become the bottleneck problem that prevents cell infiltration and tissue ingrowth into the scaffold. The combination of different techniques will be more effective to overcome this problem.