Hydralazine loaded nanodroplets combined with ultrasound-targeted microbubble destruction to induce pyroptosis for tumor treatment.

Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Engineering an extracellular matrix-functionalized, load-bearing tendon substitute for effective repair of large-to-massive tendon defects.

A significant clinical challenge in large-to-massive rotator cuff tendon injuries is the need for sustaining high mechanical demands despite limited tissue regeneration, which often results in clinical repair failure with high retear rates and long-term functional deficiencies. To address this, an innovative tendon substitute named "BioTenoForce" is engineered, which uses (i) tendon extracellular matrix (tECM)'s rich biocomplexity for tendon-specific regeneration and (ii) a mechanically robust, slow degradation polyurethane elastomer to mimic native tendon's physical attributes for sustaining long-term shoulder movement. Comprehensive assessments revealed outstanding performance of BioTenoForce, characterized by robust core-shell interfacial bonding, human rotator cuff tendon-like mechanical properties, excellent suture retention, biocompatibility, and tendon differentiation of human adipose-derived stem cells. Importantly, BioTenoForce, when used as an interpositional tendon substitute, demonstrated successful integration with regenerative tissue, exhibiting remarkable efficacy in repairing large-to-massive tendon injuries in two animal models. Noteworthy outcomes include durable repair and sustained functionality with no observed breakage/rupture, accelerated recovery of rat gait performance, and >1 cm rabbit tendon regeneration with native tendon-like biomechanical attributes. The regenerated tissues showed tendon-like, wavy, aligned matrix structure, which starkly contrasts with the typical disorganized scar tissue observed after tendon injury, and was strongly correlated with tissue stiffness. Our simple yet versatile approach offers a dual-pronged, broadly applicable strategy that overcomes the limitations of poor regeneration and stringent biomechanical requirements, particularly essential for substantial defects in tendon and other load-bearing tissues.

Feasibility of diffusion tensor imaging in cervical spondylotic myelopathy using MUSE sequence.

BACKGROUND CONTEXT: The most frequent type of spinal cord injury is cervical spondylotic myelopathy (CSM). Conventional structural magnetic resonance imaging (MRI) is the gold diagnosis standard for CSM. Diffusion tensor imaging (DTI) could reflect microstructural changes in the spinal cord by tracing water molecular diffusion in early stages of CSM. However, due to the complex local anatomical structure and small field of view of the spinal cord, the imaging effect of traditional DTI imaging on the spinal cord is limited. MUSE (MUltiplexed Sensitivity-Encoding) -DTI is a novel diffusion-weighted imaging (DWI) sequence that achieves higher signal intensity through multiple excitation acquisition. MUSE sequence may improve the quality of spinal cord DTI imaging. STUDY DESIGN: Prospective study. PURPOSE: This study aimed to investigate the clinical diagnosis value of a novel protocol of MUSE-DTI in patients with cervical spondylotic myelopathy (CSM). PATIENT SAMPLE: From August 2021 to March 2022, a total of 60 subjects (22-71 years) were enrolled, including 51 CSM patients (22 males, 29 females) and 9 healthy subjects (4 males and 5 females). Each subject underwent a MUSE-DTI examination and a clinical Japanese Orthopedic Association (JOA) scale. OUTCOME MEASURES: We measured values of FA (Fractional Anisotropy), MD (Mean Diffusivity), AD (Axial Diffusivity), and RD (Radial Diffusivity), and collected the clinical JOA scores of each subject before the MR examination. METHODS: A 3.0T MR scanner (Signa Architect, GE Healthcare) performed the MUSE-DTI sequence on each subject. The cervical canal stenosis of subjects was classified from grade 0 to grade Ⅲ according to the method of an MRI grading system. FA, MD, AD, and RD maps were generated by postprocessing MUSE-DTI data on the GE workstation. Regions of interest (ROIs) were manually drawn at the C2 vertebral body level and C2/3-C6/7 intervertebral disc levels by covering the whole spinal cord. The clinical severity of myelopathy of subjects was assessed by the clinical Japanese Orthopedic Association scale (JOA). RESULTS: MUSE-DTI can acquire a high-resolution diffusion image compared to traditional DTI. The FAMCL values showed a decreasing trend from grade 0 to grade Ⅲ, while the MDMCL, ADMCL, and RDMCL values showed an overall increasing trend. Significant differences in MDMCL, ADMCL, and RDMCL values were found between adjacent groups among grades Ⅰ-Ⅲ (p<.05). The ADC2 values in CSM patients (grade I-Ⅲ) were significantly lower than in healthy individuals (grade 0) (p=.019). The clinical JOA score has a significant correlation with FAMCL (p=.035), MDMCL (p<.001), ADMCL (p<.001), and RDMCL (p<.001) values. CONCLUSIONS: MUSE-DTI displayed a better image quality compared to traditional DTI. MUSE-DTI parameters displayed a grade-dependent trend. All the MUSE-DTI parameters at MCL were correlated with the clinical JOA scores. The ADC2 values can reflect the secondary damage of distal spinal cord. Therefore, MUSE-DTI could be a reliable biomarker for clinical auxiliary diagnosis of spinal cord injury severity in cervical spondylotic myelopathy.

Assessment of relationships between frailty and chronic pain: a bidirectional two-sample Mendelian randomisation study.

BACKGROUND: Previous observational studies have indicated a complex association between chronic pain and frailty. This study aimed to examine the bidirectional causal relationship between frailty and chronic pain and to quantify mediating effects of known modifiable risk factors. METHODS: A bidirectional two-sample Mendelian randomisation (MR) analysis was applied in this study. Summary genome-wide association statistics for frailty, as defined by both frailty index (FI) and Fried Frailty Score (FFS), pain at seven site-specific chronic pain (SSCP) (headache, facial, neck/shoulder, stomach/abdominal, back, hip and knee) and multisite chronic pain (MCP) were extracted from populations of European ancestry. Genetic instrumental variables strongly correlated with each exposure were selected. The inverse-variance-weighted method was the primary method used in the MR, supplemented by a range of sensitivity and validation analyses. Two-step MR analysis was undertaken to evaluate the mediating effects of several proposed confounders. RESULTS: Genetically predicted higher FI and FFS were associated with an increased risk of MCP and specific types of SSCP, including neck/shoulder pain, stomach/abdominal pain, back pain, hip pain and knee pain. In the reverse direction analysis, genetic liability to MCP was found to be associated with increased FI and FFS. These results remained consistent across sensitivity and validation assessments. Two-step MR suggested a mediating role for body mass index, smoking initiation, physical inactivity, educational attainment and depression. CONCLUSIONS: Our research provided genetic evidence that the association between frailty and chronic pain was bidirectional where the coexistence of both conditions will exacerbate each other.

Apparent Treatment-Resistant Hypertension in the First Year Associated with CV Mortality in PD Patients.

BACKGROUND: Few reports have focused on the association between apparent treatment-resistant hypertension (aTRH) and cardiovascular (CV) mortality in peritoneal dialysis (PD) population, thus we conducted this retrospective cohort to explore it.Patients and Methods: This was a retrospective cohort study conducted from January 2011 to January 2020 with PD patients in 4 Chinese dialysis centers. ATRH was defined according to the American College of Cardiology and American Heart Association guidelines. ATRH duration was calculated as the total number of months when patients met the diagnostic criteria in the first PD year. The primary outcome was CV mortality, and the secondary outcomes were CV events, all-cause mortality, combined endpoint (all-cause mortality and transferred to HD), and PD withdrawal (all-cause mortality, transferred to HD and kidney transplantation). Cox proportional hazards models were used to assess the association. RESULTS: A total of 1,422 patients were finally included in the analysis. During a median follow-up period of 26 months, 83 (5.8%) PD patients incurred CV mortality. The prevalence of aTRH was 24.1%, 19.9%, 24.6% at 0, 3, 12 months after PD initiation respectively. Overall, aTRH duration in the first PD year positively associated with CV mortality (per 3 months increment, adjusted HR, 1.29; 95% CI 1.10, 1.53; P=0.002). After categorized, those with aTRH duration more than 6 months presented the highest adjusted HR of 2.92. Similar results were found for secondary outcomes, except for the CV event. CONCLUSION: Longer aTRH duration in the first PD year is associated with higher CV mortality and worse long-term clinical outcomes. Larger studies are warranted to confirm these findings.

N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation.

BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS: Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS: circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS: Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.

Non-collagenous proteins, rather than the collagens, are key biochemical factors that mediate tenogenic bioactivity of tendon extracellular matrix.

Despite the growing clinical use of extracellular matrix (ECM)-based biomaterials for tendon repair, undesired healing outcomes or complications have frequently been reported. A major scientific challenge has been the limited understanding of their functional compositions and mechanisms of action due to the complex nature of tendon ECM. Previously, we have reported a soluble ECM fraction from bovine tendons (tECM) by urea extraction, which exhibited strong, pro-tenogenic bioactivity on human adipose-derived stem cells (hASCs). In this study, to advance our previous findings and gain insights into the biochemical nature of its pro-tenogenesis activity, tECM was fractionated using (i) an enzymatic digestion approach (pepsin, hyaluronidase, and chondroitinase) to yield various enzyme-digested tECM fractions; and (ii) a gelation-based approach to yield collagen matrix-enriched (CM) and non-collagenous matrix-enriched (NCM) fractions. Their tenogenic bioactivity on hASCs was assessed. Our results collectively indicated that non-collagenous tECM proteins, rather than collagens, are likely the important biochemical factors responsible for tECM pro-tenogenesis bioactivity. Mechanistically, RNA-seq analysis revealed that tECM and its non-collagenous portion induced similar transcriptional profiles of hASCs, particularly genes associated with cell proliferation, collagen synthesis, and tenogenic differentiation, which were distinct from transcriptome induced by its collagenous portion. From an application perspective, the enhanced solubility of the non-collagenous tECM, compared to tECM, should facilitate its combination with various water-soluble biomaterials for tissue engineering protocols. Our work provides insight into the molecular characterization of native tendon ECM, which will help to effectively translate their functional components into the design of well-defined, ECM biomaterials for tendon regeneration. STATEMENT OF SIGNIFICANCE: Significant progress has been made in extracellular matrix (ECM)-based biomaterials for tendon repair. However, their effectiveness remains debated, with conflicting research and clinical findings. Understanding the functional composition and mechanisms of action of ECM is crucial for developing safe and effective bioengineered scaffolds. Expanding on our previous work with bovine tendon ECM extracts (tECM) exhibiting strong pro-tenogenesis activity, we fractionated tECM to evaluate its bioactive moieties. Our findings indicate that the non-collagenous matrix within tECM, rather than the collagenous portions, plays a major role in the pro-tenogenesis bioactivity on human adipose-derived stem cells. These insights will drive further optimization of ECM-based biomaterials, including our advanced method for preparing highly soluble, non-collagenous matrix-enriched tendon ECM for effective tendon repair.

Knockdown of FOXRED2 restrains proliferation, invasion and migration of human melanoma cells.

Objectives: This experiment investigated the role of the FAD-dependent oxidoreductase domain-containing 2 (FOXRED2) in the development of cutaneous malignant melanoma. Methods: We explored the expression and prognostic effects of FOXRED2 in cutaneous malignant melanoma by performing bioinformatics analyses and immunohistochemical staining experiments and verified the biological influence of FOXRED2 on human melanoma cells using in vitro experiments. Results: FOXRED2 expression was significantly higher in cutaneous malignant melanoma compared to normal skin and nevus tissues and closely associated with prognosis. The expression levels of FOXRED2 mRNA and protein were significantly upregulated in human melanoma cell lines, and knocking down FOXRED2 expression inhibits proliferation, invasion, and migration, promotes apoptosis, and alters tumor cell biology in A2058 and A375 cells. Conclusion: FOXRED2 may play a crucial role in the development and progression of cutaneous malignant melanoma.

The Chinese lexicon of deaf readers: A database of character decisions and a comparison between deaf and hearing readers.

We present a psycholinguistic study investigating lexical effects on simplified Chinese character recognition by deaf readers. Prior research suggests that deaf readers exhibit efficient orthographic processing and decreased reliance on speech-based phonology in word recognition compared to hearing readers. In this large-scale character decision study (25 participants, each evaluating 2500 real characters and 2500 pseudo-characters), we analyzed various factors influencing character recognition accuracy and speed in deaf readers. Deaf participants demonstrated greater accuracy and faster recognition when characters were more frequent, were acquired earlier, had more strokes, displayed higher orthographic complexity, were more imageable in reference, or were less concrete in reference. Comparison with a previous study of hearing readers revealed that the facilitative effect of frequency on character decision accuracy was stronger for deaf readers than hearing readers. The effect of orthographic-phonological regularity differed significantly for the two groups, indicating that deaf readers rely more on orthographic structure and less on phonological information during character recognition. Notably, increased stroke counts (i.e., higher orthographic complexity) hindered hearing readers but facilitated recognition processes in deaf readers, suggesting that deaf readers excel at recognizing characters based on orthographic structure. The database generated from this large-scale character decision study offers a valuable resource for further research and practical applications in deaf education and literacy.

Construction of clinical research nurse training program based on position competence.

BACKGROUND: As one of the most important members in clinical trials, the number of clinical research nurses (CRN) can't keep up with the growth of experimental projects, so it is urgent to build clinical research training and strengthen the background knowledge of nurses. AIM: To construct CRN training program based on position competence, accelerate the construction of CRN talent pool, and provide scientific guidance significance for CRN training. METHODS: Based on the position competence model, combined with literature research and qualitative interview results, the first draft was prepared of the CRN training program. Two rounds of correspondence with 16 experts were conducted using the Delphi method to determine the training program. RESULTS: The effective recovery rate of the expert correspondence questionnaire was 100% and the authority coefficients of the 2 rounds of experts were 0.826 and 0.895. Finally, 4 first-level indicators and determine 15 s-level indicators of training objectives. The training program included 4 first-level indicators, training requirements, content, methods, assessment and evaluation, 15 s-level indicators, and 74 third-level indicators. CONCLUSION: The CRN training program based on position competence is scientific and extendable, providing a basis for participation in CRN training.

An improved multi-scale gradient generative adversarial network for enhancing classification of colorectal cancer histological images.

Introduction: Deep learning-based solutions for histological image classification have gained attention in recent years due to their potential for objective evaluation of histological images. However, these methods often require a large number of expert annotations, which are both time-consuming and labor-intensive to obtain. Several scholars have proposed generative models to augment labeled data, but these often result in label uncertainty due to incomplete learning of the data distribution. Methods: To alleviate these issues, a method called InceptionV3-SMSG-GAN has been proposed to enhance classification performance by generating high-quality images. Specifically, images synthesized by Multi-Scale Gradients Generative Adversarial Network (MSG-GAN) are selectively added to the training set through a selection mechanism utilizing a trained model to choose generated images with higher class probabilities. The selection mechanism filters the synthetic images that contain ambiguous category information, thus alleviating label uncertainty. Results: Experimental results show that compared with the baseline method which uses InceptionV3, the proposed method can significantly improve the performance of pathological image classification from 86.87% to 89.54% for overall accuracy. Additionally, the quality of generated images is evaluated quantitatively using various commonly used evaluation metrics. Discussion: The proposed InceptionV3-SMSG-GAN method exhibited good classification ability, where histological image could be divided into nine categories. Future work could focus on further refining the image generation and selection processes to optimize classification performance.

The MYBL2-CCL2 axis promotes tumor progression and resistance to anti-PD-1 therapy in ovarian cancer by inducing immunosuppressive macrophages.

BACKGROUND: An immunosuppressive tumor microenvironment in ovarian cancer facilitates tumor progression and resistance to immunotherapy. The function of MYB Proto-Oncogene Like 2 (MYBL2) in the tumor microenvironment remains largely unexplored. METHODS: A syngeneic intraovarian mouse model, flow cytometry analysis, and immunohistochemistry were used to explore the biological function of MYBL2 in tumor progression and immune escape. Molecular and biochemical strategies-namely RNA-sequencing, western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, multiplex immunofluorescence, chromatic immunoprecipitation assay (CHIP) and luciferase assay-were used to reveal the mechanisms of MYBL2 in the OVC microenvironment. RESULTS: We found tumor derived MYBL2 indicated poor prognosis and selectively correlated with tumor associated macrophages (TAMs) in ovarian cancer. Mechanically, C-C motif chemokine ligand 2 (CCL2) transcriptionally activated by MYBL2 induced TAMs recruitment and M2-like polarization in vitro. Using a syngeneic intraovarian mouse model, we identified MYBL2 promoted tumor malignancyand increased tumor-infiltrating immunosuppressive macrophages. Cyclin-dependent kinase 2 (CDK2) was a known upstream kinase to phosphorylate MYBL2 and promote its transcriptional function. The upstream inhibitor of CDK2, CVT-313, reprogrammed the tumor microenvironment and reduced anti-PD-1 resistance. CONCLUSIONS: The MYBL2/CCL2 axis contributing to TAMs recruitment and M2-like polarization is crucial to immune evasion and anti-PD-1 resistance in ovarian cancer, which is a potential target to enhance the efficacy of immunotherapy.

Novel insights into anticancer mechanisms of elesclomol: More than a prooxidant drug.

As an essential micronutrient for humans, the metabolism of copper is fine-tuned by evolutionarily conserved homeostatic mechanisms. Copper toxicity occurs when its concentration exceeds a certain threshold, which has been exploited in the development of copper ionophores, such as elesclomol, for anticancer treatment. Elesclomol has garnered recognition as a potent anticancer drug and has been evaluated in numerous clinical trials. However, the mechanisms underlying elesclomol-induced cell death remain obscure. The discovery of cuproptosis, a novel form of cell death triggered by the targeted accumulation of copper in mitochondria, redefines the significance of elesclomol in cancer therapy. Here, we provide an overview of copper homeostasis and its associated pathological disorders, especially copper metabolism in carcinogenesis. We summarize our current knowledge of the tumor suppressive mechanisms of elesclomol, with emphasis on cuproptosis. Finally, we discuss the strategies that may contribute to better application of elesclomol in cancer therapy.

Aqueous-Cellulose-Solvent-Derived Changes in Cellulose Nanocrystal Structure and Reinforcing Effects.

Cellulose nanocrystals as reinforcing agents have received considerable interest, and their dimension mainly depends on the original sources of cellulose. We intend to manually modulate the morphology of cellulose nanocrystals by treating them with cellulose solvents so that we can explore their reinforcing capacity. In this work, waste cotton fabric was processed in two aqueous solvents (a sulfuric acid aqueous solution and a NaOH/urea aqueous solution), and the regenerated cellulose was used to produce cellulose nanocrystals using acid hydrolysis. The results revealed that the nanocrystals (RCNC-H) obtained after the treatment in sulfuric acid had a hybrid crystalline structure and a needle-like shape with an aspect ratio of about 15.2, while cotton fabric was completely dissolved in the NaOH/urea aqueous solution, and the regenerated nanocrystals (RCNC-N) displayed a typical crystalline form of cellulose II with a higher crystallinity and a shorter rod-like shape with an aspect ratio of about 6.3. The reinforcing effects of RCNC-H and RCNC-N were evaluated using polyvinyl alcohol (PVA) films as a model, where the addition of RCNC-H resulted in a relatively better tensile strength and oxygen barrier property, and the PVA/RCNC-N films had a slightly lower water vapor permeability. Therefore, this work suggests a new possibility for altering the naturally formed nanostructure of cellulose for different applications.

Machine learning-driven 3D plasmonic cellulose sensor for in situ rapid SERS detection of bisphenol compounds in water sample.

Rapid component separation and accurate identification of bisphenols compounds (BPs) in real water sample remain an attractive challenge due to the trace amounts and structural similarities of BPs, and complexity of real samples. Here, we designed and synthesized chemically modified cellulose p-toluenesulfonate (CTSA) to encapsulate octadecylamine-modified gold nanoparticles (Au-ODA), obtaining 3D plasmonic cellulose (Au@CTSA). Simultaneously, by virtue of the high surface area in the 3D network of CTSA and the solvent volatile deposition, BPs in water were in situ extracted and concentrated in Au@CTSA microspheres. Since the 3D network of Au@CTSA supports the formation of "hotspots", the number of "hotspots" available is greatly improved, enabling excellent SERS detection of BPs. Based on the collected SERS spectra, machine learning was utilized to analyze the overall profile of BPs, which eliminated the subjective judgment of the concentration by the Au@CTSA sensor using a single characteristic peak. In this way, the accuracy of identification of BPs was significantly improved. The machine learning-driven Au@CTSA sensor realized the detection of traces bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF) in water sample, pushing quantitative detection of different concentrations of BPs and contributing facile indicators for water quality monitoring.

Emerging insights into mechanisms of trastuzumab resistance in HER2-positive cancers.

HER2 is an established therapeutic target in breast, gastric, and gastroesophageal junction carcinomas with HER2 overexpression or genomic alterations. The humanized monoclonal antibody trastuzumab targeting HER2 has substantially improved the clinical outcomes of HER2-positive patients, yet the inevitable intrinsic or acquired resistance to trastuzumab limits its clinical benefit, necessitating the elucidation of resistance mechanisms to develop alternate therapeutic strategies. This review presents an overview of trastuzumab resistance mechanisms involving signaling pathways, cellular metabolism, cell plasticity, and tumor microenvironment, particularly discussing the prospects of developing rational combinations to improve patient outcomes.

Analysis of patient medication compliance and quality of life of physician-pharmacist collaborative clinics for T2DM management in primary healthcare in China: A mixed-methods study.

Background: Physician-pharmacist collaboration is a well-established care mode for the management of type 2 diabetes mellitus (T2DM) in developed countries, but no study has been conducted in primary healthcare in China. This study aims to evaluate the effects of physician-pharmacist collaborative clinics to manage T2DM in primary healthcare in China, and to better understand the factors influencing the implementation of physician-pharmacist collaborative clinics. Methods: Two hundred and sixty-seven patients involved in a 12-month randomized controlled trial were assigned to physician-pharmacist collaborative clinics and usual clinics, completing surveys regarding medication compliance, quality of life (QoL) and care-seeking behavior at the baseline, 3rd, 6th, 9th and 12th month respectively, and diabetes knowledge at baseline and 12th month. A sample of twenty-two Patients, nine physicians and twelve pharmacists participated in semi-structured face-to-face interviews. The quantitative and qualitative data was integrated by triangulation. Results: Patients in physician-pharmacist collaborative clinics had significant improvements in medication compliance (p = 0.009), QoL (p = 0.036) and emergency visits (p = 0.003) over the 12-month. Pairwise comparison showed the medication compliance score in the intervention group had been significantly improved at 3rd month (p = 0.001), which is more rapidly than that in the control group at 9th month (p = 0.030). Factors influencing the implementation of physician-pharmacist collaborative clinics were driven by five themes: pharmaceutical service, team-base care, psychological support, acceptability of care and barriers to implementation. Conclusion: Integration of quantitative and qualitative findings showed the effectiveness of physician-pharmacist collaborative clinics in patient medication compliance and QoL in primary healthcare. The qualitative study uncovered barriers in insufficient clinical experience and understaffing of pharmacist. Therefore, the professional training of the primary pharmacist team should be improved in the future. Clinical Trial Registration: clinicaltrials.gov, identifier ChiCTR2000031839.

MKRN1/2 serve as tumor suppressors in renal clear cell carcinoma by regulating the expression of p53.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) belongs to renal cell carcinoma which is a very aggressive malignant tumor with poor prognosis and high mortality. The MKRN family includes three members MKRN1, MKRN2 and MKRN3, which are closely related to cancers, and have been involved in many studies. OBJECTIVE: This study aimed to explore the roles of MKRN family in KIRC. METHODS: The expression of MKRNs was analyzed using the UALCAN database, prognostic analysis was performed with the GEPIA2 and Kaplan-Meier Plotter database, and correlation analysis was assessed by GEPIA2. The CCK-8 and colony formation assay were performed to detect cell proliferation, wound healing assays were performed to detect cell migration, cell cycles were detected by flow cytometry analysis, GST pull-down and co-immunoprecipitation assays were performed to detect the interaction of proteins, and the expression of MKRNs, p53 and other proteins were detect by immunoblotting analysis or quantitative PCR (qPCR). RESULTS: MKRN1 and MKRN2 were lowly expressed in KIRC samples compared to the corresponding normal tissues, and KIRC patients with high levels of MKRN1 and MKRN2 showed higher overall survival (OS) and disease free survival (DFS) rates. The overexpression of MKRN1 and MKRN2 inhibited the proliferation of human KIRC cells by arresting the cell cycles, but shows little effect on cells migration. The expression of MKRN1 and MKRN2 are correlated, and MKRN1 directly interacts with MKRN2. Moreover, both MKRN1 and MKRN2 were closely correlated with the expression of TP53 in KIRC tumor, and promoted the expression of p53 both at protein and mRNA levels. CONCLUSIONS: Our study suggests that MKRN1 and MKRN2 serve as tumor suppressors in KIRC, and act as promising therapeutic targets for KIRC treatment.