Stroke-like episodes in patients with adult-onset neuronal intranuclear inclusion disease and patients with late-onset MELAS: A comparative study.

OBJECTIVE: To delineate the characteristics of stroke-like episodes (SLEs) in patients with adult-onset neuronal intranuclear inclusion disease (NIID) and to compare these characteristics with those of patients with MELAS. METHODS: Twenty-three adult-onset NIID patients who presented with acute or subacute brain disorders and 13 late-onset MELAS patients were enrolled in the study. Patients with NIID were categorized into the SLEs group and the encephalopathy-like episodes (ELEs) group according to the associated stroke-like lesions (SLLs) findings. Clinical characteristics were compared between the SLEs group and the ELEs group among NIID patients and between NIID patients with SLEs and MELAS patients. RESULTS: Eleven (47.8%) NIID patients who manifested acute or subacute brain disorders had detectable associated SLLs and were categorized into SLEs group. SLEs patients were more likely to report fever, headache, and seizures instead of sleep disorders than ELEs patients. Four (36.4%) NIID patients with SLEs absence of diagnostic or suggestive NIID imaging features. The clinical manifestations, laboratory test results, and neuroimaging and muscle biopsy histological features of NIID patients with SLEs majorly overlapped with those of late-onset MELAS patients. Older age at the first SLE (OR [95% CI], 1.203 [1.045-1.384]), symptoms of movement disorders on admission (OR [95% CI], 9.625 [1.378-67.246]), and white matter hyperintensity in corpus callosum (OR [95% CI], 16.00 [1.542-166.46]) associated with the NIID diagnosis in patients with SLEs. INTERPRETATION: NIID patients with SLEs exhibit evident features of mitochondrial disorders. Interventions aimed at mitochondrial dysfunction might be a promising therapeutic approach for treating this disease.

Risk factors and clinical impact of seroma formation following laparoscopic inguinal hernia repair: a retrospective study.

BACKGROUND: Although laparoscopic inguinal hernia repair (LIHR) has advantages over open surgery, postoperative seroma formation remains an issue. This study aimed to investigate the risk factors and clinical outcomes of seroma formation in patients undergoing LIHR. METHODS: From January 2016 to March 2023, clinical data of patients who underwent LIHR were retrospectively analyzed. Patients who developed seroma and those who did not were classified into the seroma and non-seroma groups, respectively. The demographic and clinical characteristics were compared between the two groups. Univariate and multivariate logistic regression analyses were performed for variables of interest. The receiver operating characteristic curve was used to evaluate the risk factors of the binary logistic model, and the cutoff value for each risk factor was obtained. RESULTS: Data of 128 patients were evaluated. Compared with patients in the non-seroma group, those in the seroma group had a higher body mass index (BMI) (P < 0.001), more direct hernias (P < 0.001), larger hernial orifice size (P < 0.001), more laparoscopic total extraperitoneal hernioplasty (TEP) (P < 0.001), more frequent reduction of hernial sac (P = 0.011), and lower preoperative serum albumin level (PSAL) (P < 0.001). Multivariate logistic regression analyses performed on these variables showed that high BMI (P = 0.005), large hernial orifice (P = 0.001), TEP (P = 0.033), and low PSAL (P = 0.009) were risk factors for seroma formation. Compared with the non-seroma group, the seroma group exhibited a higher numerical rating scale score for postoperative pain (P < 0.001), and longer hospital stays (P = 0.032). CONCLUSIONS: BMI (> 24.5 kg/m2), hernial orifice size (> 2.5 cm), TEP, and PSAL (< 32.5 g/L) were independent risk factors of postoperative seroma formation in patients who underwent LIHR. Although most seromas resolve spontaneously without surgical intervention, seroma formation results in increased patient pain and prolonged hospital stay.

Single nucleus/cell RNA-seq of the chicken hypothalamic-pituitary-ovarian axis offers new insights into the molecular regulatory mechanisms of ovarian development.

The hypothalamic-pituitary-ovarian (HPO) axis represents a central neuroendocrine network essential for reproductive function. Despite its critical role, the intrinsic heterogeneity within the HPO axis across vertebrates and the complex intercellular interactions remain poorly defined. This study provides the first comprehensive, unbiased, cell type-specific molecular profiling of all three components of the HPO axis in adult Lohmann layers and Liangshan Yanying chickens. Within the hypothalamus, pituitary, and ovary, seven, 12, and 13 distinct cell types were identified, respectively. Results indicated that the pituitary adenylate cyclase activating polypeptide (PACAP), follicle-stimulating hormone (FSH), and prolactin (PRL) signaling pathways may modulate the synthesis and secretion of gonadotropin-releasing hormone (GnRH), FSH, and luteinizing hormone (LH) within the hypothalamus and pituitary. In the ovary, interactions between granulosa cells and oocytes involved the KIT, CD99, LIFR, FN1, and ANGPTL signaling pathways, which collectively regulate follicular maturation. The SEMA4 signaling pathway emerged as a critical mediator across all three tissues of the HPO axis. Additionally, gene expression analysis revealed that relaxin 3 (RLN3), gastrin-releasing peptide (GRP), and cocaine- and amphetamine regulated transcripts (CART, also known as CARTPT) may function as novel endocrine hormones, influencing the HPO axis through autocrine, paracrine, and endocrine pathways. Comparative analyses between Lohmann layers and Liangshan Yanying chickens demonstrated higher expression levels of GRP, RLN3, CARTPT, LHCGR, FSHR, and GRPR in the ovaries of Lohmann layers, potentially contributing to their superior reproductive performance. In conclusion, this study provides a detailed molecular characterization of the HPO axis, offering novel insights into the regulatory mechanisms underlying reproductive biology.

TransCell: In Silico Characterization of Genomic Landscape and Cellular Responses by Deep Transfer Learning.

Gene expression profiling of new or modified cell lines becomes routine today; however, obtaining comprehensive molecular characterization and cellular responses for a variety of cell lines, including those derived from underrepresented groups, is not trivial when resources are minimal. Using gene expression to predict other measurements has been actively explored; however, systematic investigation of its predictive power in various measurements has not been well studied. Here, we evaluated commonly used machine learning methods and presented TransCell, a two-step deep transfer learning framework that utilized the knowledge derived from pan-cancer tumor samples to predict molecular features and responses. Among these models, TransCell had the best performance in predicting metabolite, gene effect score (or genetic dependency), and drug sensitivity, and had comparable performance in predicting mutation, copy number variation, and protein expression. Notably, TransCell improved the performance by over 50% in drug sensitivity prediction and achieved a correlation of 0.7 in gene effect score prediction. Furthermore, predicted drug sensitivities revealed potential repurposing candidates for new 100 pediatric cancer cell lines, and predicted gene effect scores reflected BRAF resistance in melanoma cell lines. Together, we investigated the predictive power of gene expression in six molecular measurement types and developed a web portal (http://apps.octad.org/transcell/) that enables the prediction of 352,000 genomic and cellular response features solely from gene expression profiles.

Impact of dynamic changes of tumor marker in neoadjuvant chemotherapy-treated triple-negative gastric cancer patients: a multi-center study.

BACKGROUND: Independent and valid prognostic predictors for locally advanced gastric cancer (LAGC) patients with non-elevated serum tumor markers (Triple-negative: CA199 < 37U/ml, CEA < 5 µg/ml and CA125 < 35U/ml) before and after neoadjuvant chemotherapy (NACT) remain unclear. METHODS: A total of 352 LAGC patients treated with NACT(NLAGC) from two centers were included. Of the 156 were Triple-negative patients. CA72-4 trajectory groupings was defined as longitudinal changes in CA72-4 levels before and after NACT to identify different potential subgroups and to compare recurrence-free survival (RFS) and overall survival (OS) among subgroups. The predictive performance of the nomogram-trajectory was evaluated using the area under the receiver operating characteristic curve(AUC), decision curve analysis, and C-index. RESULTS: In the Triple-negative patients, the Stable group had significantly worse 3-year OS than the Normal, Elevated, and Descend groups(3-year OS: 53.9% vs. 77.9% vs. 73.5% vs. 87.7%;P = 0.002). Cox multivariate analysis showed that CA72-4 trajectory groupings (Stable group: HR:3.442, 95%CI[1.574-7.528], P = 0.002) was an independent prognostic risk factor. In addition, the C-index and AUC values based on the nomogram-trajectory were significantly higher than those of ypTNM staging (C-index: 0.788 vs. 0.719,P < 0.001;AUC: 0.800 vs. 0.667,P < 0.001). Furthermore, The survival analysis revealed that the 3-year OS of the Low-Risk group of nomogram scores was significantly better than that of the High-Risk group(3-year OS:84.7% vs. 29.1%). And the Low-Risk group had the lower cumulative risk of recurrence (P < 0.001). CONCLUSION: The CA72-4 trajectory groupings were an independent prognostic factor for NLAGC Triple-negative patients. The predictive efficacy of the Nomogram-trajectory was significantly better than the ypTNM.

Partial hepatectomy versus interventional treatment in patients with hepatitis B virus-related hepatocellular carcinoma and clinically significant portal hypertension: a randomized comparative clinical trial.

BACKGROUND: The widely accepted view that portal hypertension (PHT) is a contraindication to hepatectomy for patients with hepatocellular carcinoma (HCC) is being increasingly challenged. The long-term survival outcomes and safety of partial hepatectomy versus interventional treatment using ablation with or without pre-ablation transarterial chemoembolization (TACE) in patients with HBV-related HCC within the Milan criteria and with clinically significant PHT were compared in this study. METHODS: This open-label randomized clinical trial was conducted on consecutive patients with clinically PHT and hepatitis B virus (HBV)-related HCC with tumors which were within the Milan criteria. These patients were randomized 1:1 to receive either partial hepatectomy or interventional treatment between December 2012 and June 2018. The primary endpoint was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and therapeutic safety. RESULTS: Each of the 2 groups had 80 patients. The 1-, 3- and 5-year OS rates in the partial hepatectomy group and the interventional treatment group were 95.0%, 86.2%, 69.5% versus 93.8%, 77.5%, 64.9%, respectively (P = 0.325). The corresponding RFS rates were 78.8%, 55.0%, 46.2% versus 71.3%, 52.5%, 45.0%, respectively (P = 0.783). The partial hepatectomy group had a higher complication rate compared to the interventional group (67.5% vs. 20%, P < 0.001). However, the differences were mainly in Clavien-Dindo Grade I complications (P < 0.001), while not significant in Grade II/III/IV/V (All P > 0.05). CONCLUSIONS: This study shows that partial hepatectomy treatment did not meet prespecified significance for improved OS and RFS compared to interventional treatment for patients with HBV-related HCC within the Milan criteria and with clinically significant PHT. However, partial hepatectomy is still a safe procedure and should be considered as a treatment option rather than a contraindication.

Efficacy of neoadjuvant chemotherapy combined with prophylactic intraperitoneal hyperthermic chemotherapy for patients diagnosed with clinical T4 gastric cancer who underwent laparoscopic radical gastrectomy: a retrospective cohort study based on propensity score matching.

BACKGROUND: Clinical T4 (cT4) stage gastric cancer presents with frequent postoperative recurrence and poor prognosis. This study is to evaluate the oncological efficacy of laparoscopic radical total gastrectomy combined with postoperative prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with cT4N + M0 gastric cancer who received neoadjuvant chemotherapy. METHODS: We reviewed the clinicopathological data of 174 patients with clinical T4 gastric cancer who underwent neoadjuvant chemotherapy followed by laparoscopic radical total gastrectomy between June 2017 and December 2021. Among them, 142 were included in the non-HIPEC group, and 32 in the HIPEC group. Patients in both groups were paired based on propensity score in a 2:1 ratio to assess disparities in tumor recurrence and long-term survival. RESULTS: After matching, there were no significant differences in the clinicopathological data between the two groups. The peritoneum (16.1%) and distant organs (10.9%) were the most frequent locations for recurrence. Prior to matching, the recurrence rates were similar at all sites for both groups. Compared with those in the non-HIPEC cohort, the recurrence rates at all sites, the lung, and the peritoneum were notably lower in the HIPEC cohort. Prior to matching, the 3-year overall survival and disease-free survival rates were similar between the two groups; following matching, the HIPEC group exhibited notably greater survival rates than did the non-HIPEC group. The disparities in survival rates between the groups became even more pronounced after conducting a stratified analysis among patients with stage III disease. CONCLUSIONS: Neoadjuvant chemotherapy combined with prophylactic HIPEC after laparoscopic radical gastrectomy can effectively reduce the rate of peritoneal metastasis in patients with cT4N + M0 advanced gastric cancer and significantly improve the prognosis of such patients, which is of great clinical value.

Improved Thoracoscopic-Assisted Surgery for the Treatment of Metastatic Thoracic Vertebral Tumors.

The significant progress made in the diagnosis and treatment of malignant tumors has led to improved patient survival rates. However, the metastatic spread of these tumors to the thoracic vertebrae remains a significant challenge, often resulting in bone-related adverse events, such as pathological fractures and severe complications. To address this issue, a refined multidisciplinary approach has been explored, which utilizes thoracoscopic techniques for tumor resection and spinal interventions. Thoracoscopic techniques offer a minimally invasive alternative to traditional open surgical methods, aiming to reduce the overall trauma experienced by patients. By leveraging the advantages of thoracoscopy, clinicians can effectively resect metastatic tumors within the thoracic vertebrae while minimizing the impact on surrounding tissues and structures. This approach, combined with targeted spinal interventions, has the potential to improve patient outcomes and quality of life by mitigating the debilitating effects of pathological fractures and other complications associated with metastatic bone disease. The implementation of this multidisciplinary strategy, incorporating thoracoscopic tumor resection and spinal interventions, represents a promising avenue for the management of metastatic tumors within the thoracic vertebrae. Further research and clinical evaluation are necessary to fully elucidate the long-term benefits and establish the optimal treatment protocols for this patient population, ultimately enhancing the care and outcomes for individuals afflicted by this challenging condition.

[Mechanism of Paeoniae Radix Rubra and Aconiti Lateralis Radix Praeparata herbal pair in promoting hepatocellular regeneration in chronic acute liver failure based on HGF/PI3K/Akt signaling axis].

Based on the hepatocyte growth factor(HGF)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling axis, this study investigated the therapeutic effect of Paeoniae Radix Rubra and Aconiti Lateralis Radix Praeparata(PRR-ALRP) her-bal pair on acute-on-chronic liver failure(ACLF) rats and its impact on hepatocellular regeneration. The rat model of ACLF was constructed by subcutaneous and tail vein injection of bovine serum albumin combined with intraperitoneal injection of lipopolysaccharides(LPS)+D-galactosamine(D-GalN). The rats were divided into normal control(NC) group, model(vehicle) group, PRR-ALRP(5.85 g·kg~(-1)) group, and hepatocyte growth factor granules(HGFG, 4.05 g·kg~(-1)) group. Hematoxylin-eosin(HE) staining was used to observe pathological changes in rat liver tissues. Serum alanine aminotransferase(ALT), aspartate transaminase(AST), and total bilirubin(TBIL) were detected using an automatic biochemical analyzer. The levels of interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) inflammatory factors were detected by ELISA. Immunofluorescence staining was used to detect the positive expression of proliferating cell nuclear antigen(PCNA), antigen identified by monoclonal antibody(Ki67), and cell cycle protein B1(CyclinB1). Real-time fluorescence-based quantitative polymerase chain reaction(RT-qPCR) and Western blot were used to detect the mRNA and protein expression levels of HGF, growth factor receptor-bound protein 1(Gab1), PI3K, Akt, phosphorylated PI3K(p-PI3K), and phosphorylated Akt(p-Akt). The results showed that compared with the vehicle group, the PRR-ALRP group had reduced liver tissue pathological scores, improved liver function, and reduced inflammatory response, with enhanced PCNA, Ki67, and CyclinB1 fluorescence expression. Furthermore, compared with the model group, the PRR-ALRP group showed upregulated expression of HGF and Gab1 proteins, as well as activation of PI3K and Akt phosphorylation. These findings suggest that PRR-ALRP herbal pair exerts anti-liver failure effects by alleviating hepatocyte inflammatory damage and promoting hepatocellular regeneration, and its specific regulatory mechanism may be related to the activation of the HGF/PI3K/Akt signaling pathway.

Nickel-Catalyzed Reductive Dicarbofunctionalization of 1,3-Dienes with Aziridines and (Het)Aryl Electrophiles.

A three-component reductive 1,4-dicarbofunctionalization of 1,3-dienes with aziridines and (het)aryl electrophiles was realized. The combination of Ni catalysis with Mn powder as a final reductant enables the direct formation of a Csp2-Csp3 and a Csp3-Csp3 bond at one time. This protocol afforded a convenient approach to the synthesis of ß-arylethylamines bearing various functionals and heterocyclic groups. The utility of this reaction was also demonstrated by scale-up preparation, late-stage modification of bioactive molecules, and diverse transformations.

Noninvasive Detection of the Skin Structure and Inversed Retrieval of Chromophore Information Based on Diffuse Reflectance Spectroscopy.

The detection of skin's structure lays the foundation for personalized laser surgery of vascular skin disease, which can be noninvasively achieved by diffuse reflectance spectroscopy (DRS). A two-step inverse Monte Carlo radiation method based on DRS under two source-detector separations was proposed to quantify the skin structure, including chromophore concentration (melanin fm and hemoglobin fb), epidermal thickness tepi, average vessel diameter Dves, depth dpws and thickness tpws of the vascular layer for diseased skin. The method fitted the simulated DRS to the measured DRS iteratively, differences between which were described by a specific objective function to amplify blood absorption at 500-600 nm, and Dves, dpws, and tpws were estimated based on fm, fb, and tpws fitted in the first step. The results showed that the two-step method dramatically improve the inversion accuracy with mean errors of fm, fb, tpws, and dpws less than 5%.

Ultrasound Genomics Reveals a Signature for Predicting Breast Cancer Prognosis and Therapy Response.

Background: Breast cancer (BC) in women is the most common malignancy worldwide, but there is still a lack of validated tools to accurately assess patient prognosis and response to available chemotherapy treatment regimens. Method: We collected ultrasound images and transcriptome data of BC from our breast center and public database. Key ultrasound features were then identified by using the support vector machine (SVM) algorithm and correlated with prognostic genes. Long-term survival-related genes were identified through differential expression analysis, and a prognostic evaluation model was established by using Cox regression. In addition, VPS28 from the model was identified as a promising biomarker for BC. Results: Using univariate logistic regression and SVM algorithms, we identified 12 ultrasound features significantly associated with chemotherapy response. Subsequent correlation and differential expression analyses linked 401 genes to these features, from which five key signature genes were derived using Lasso and multivariate Cox regression models. This signature not only facilitates the stratification of patients into risk-specific treatment pathways but also predicts their chemotherapy response, thus supporting personalized medicine in clinical settings. Notably, VPS28, in the signature, emerged as a significant biomarker, strongly associated with poor prognosis, greater tumor invasiveness, and differing expression across demographic groups. Conclusion: In this study, we use ultrasound genomics to reveal a signature that can provide an effective tool for prognostic assessment and predicting chemotherapy response in patients with BC.

Imputing abundance of over 2,500 surface proteins from single-cell transcriptomes with context-agnostic zero-shot deep ensembles.

Cell surface proteins serve as primary drug targets and cell identity markers. Techniques such as CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) have enabled the simultaneous quantification of surface protein abundance and transcript expression within individual cells. The published data have been utilized to train machine learning models for predicting surface protein abundance solely from transcript expression. However, the small scale of proteins predicted and the poor generalization ability of these computational approaches across diverse contexts (e.g., different tissues/disease states) impede their widespread adoption. Here, we propose SPIDER (surface protein prediction using deep ensembles from single-cell RNA sequencing), a context-agnostic zero-shot deep ensemble model, which enables large-scale protein abundance prediction and generalizes better to various contexts. Comprehensive benchmarking shows that SPIDER outperforms other state-of-the-art methods. Using the predicted surface abundance of >2,500 proteins from single-cell transcriptomes, we demonstrate the broad applications of SPIDER, including cell type annotation, biomarker/target identification, and cell-cell interaction analysis in hepatocellular carcinoma and colorectal cancer. A record of this paper's transparent peer review process is included in the supplemental information.

Conjugation of TLR7 and TLR7/8 agonists onto weak protein antigen via versatile oxime ligation for enhanced vaccine efficacy.

Protein-based subunit vaccines are weakly immunogenic, and developing self-adjuvanting vaccines with adjuvant conjugated to antigen is a promising approach for generating optimal immune responses. Here, we report a novel adjuvant-protein conjugate vaccine based on versatile oxime ligation technique. Firstly, the adjuvant properties of a series of TLR7 and TLR7/8 small molecule agonists in self-adjuvanting vaccines were systematically compared by coupling them to proteins in consistent ratio via p-carboxybenzaldehyde (p-CBA) for the first time. All conjugate vaccines induced cytokine secretion in murine and human macrophages in vitro, and promoted specific antibody production in vivo. Notably, a conjugate containing imidazoquinoline TLR7/8 agonist (TLR7/8a1) showed the greatest enhancement in Th1/2 balanced antibody response. To minimize the interference with the protein antigenic integrity, we further developed a systematic glycoconjugation strategy to conjugate this TLR7/8a1 onto the glycan chains of SARS-CoV-2 S1 glycoprotein via oxime ligation, in which S1 containing different numbers of aldehyde groups were obtained by differential periodate oxidation. The resulting TLR7/8a1-S1 conjugate triggered a potent humoral and cellular immunity in vivo. Together these data demonstrate the promise of these TLR7 and TLR7/8 agonists as effective built-in adjuvants, and the versatile oxime ligation strategy might broaden potential applications in designing different conjugate vaccines.

Production of high calorific value hydrogen-rich combustible gas by supercritical water gasification of straw assisted by machine learning.

This article reveals the basic laws of straw supercritical water gasification (SCWG) and provides basic experimental data for the effective utilization of straw. The paper studied the impact of three operational conditions on the production of high-calorific value hydrogen-rich combustible gases through SCWG of straw within a quartz tube reactor. The findings reveal that elevated reaction temperatures, extended residence times, and reduced feedstock concentrations favor the SCWG of straw. When combustible gas contains carbon dioxide, the maximum low heating value (LHV) of the gas is 21 MJ/Nm3. Upon removing carbon dioxide, the LHV of the gas reached 38 MJ/Nm3. Subsequently, a machine learning (ML) model was developed to forecast gas yield and LHV during the SCWG process. The results demonstrate that the model exhibits robust generalization capabilities. ML can be extensively applied to forecast biomass SCWG processes across various operational conditions.

Therapeutic effects of chamomile volatile oil nanoemulsion/Bletilla striata polysaccharides gels on atopic dermatitis.

Atopic dermatitis (AD) is a prevalent chronic skin condition characterized by complex immune responses. Chamomile possesses potent anti-inflammatory properties and has been widely used in treating various skin diseases. This study aimed to assess the therapeutic benefits of chamomile volatile oil nanoemulsion gels (CVO-NEGs) for the treatment of AD. Chamomile volatile oil nanoemulsions (CVO-NEs) were prepared using the phase transition method, yielding spherical nanoparticles with a particle size of 19.07 nm. Subsequently, Bletilla striata polysaccharides were employed to encapsulate CVO-NEs, resulting in the formation of CVO-NEGs. In vivo studies demonstrated that the preparation of CVO-NEGs enhanced the biological activity of volatile oil in AD therapy. Histopathological results indicated that CVO-NEGs reduced skin damage, epidermal thickness, and mast cell infiltration. CVO-NEGs suppressed IgG production and reduced the levels of cytokines, including TNF-α, IL-4, and IFN-γ, in AD mice. Furthermore, flow cytometry revealed that CVO-NEGs were involved in regulating the differentiation of CD4+ T cell subsets. The immune imbalance of Th1/Th2 in AD mice can be controlled, resulting in a reduction in the hypersensitivity reaction caused by excessive Th2 activation. In conclusion, the present study confirms that CVO-NEGs have the potential to serve as an effective alternative treatment for AD.

PpIX-enabled fluorescence-based detection and photodynamic priming of platinum-resistant ovarian cancer cells under fluid shear stress.

Over 75% percent of ovarian cancer patients are diagnosed with advanced-stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build-up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi-line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced-stage ovarian cancer will relapse and succumb to platinum-resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial-to-mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS-induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro-drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence-based biomarker of FSS-induced platinum resistance. Additionally, this study investigates the efficacy of PpIX-enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov-3 and NIH:OVCAR-3 cells, two representative cell lines for high-grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA-PpIX-mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX-mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence-based indicator, and mediator of PDP, to target chemoresistance in the context of FSS.

5-Aminolevulinic acid-mediated photodynamic therapy in combination with kinase inhibitor lapatinib enhances glioblastoma cell death.

5-Aminolevulinic acid (ALA) is an intraoperative imaging agent approved for protoporphyrin IX (PpIX) fluorescence-guided resection of glioblastoma (GBM). It is currently under clinical evaluation for photodynamic therapy (PDT) after the completion of GBM surgery. We previously showed that lapatinib, a clinical kinase inhibitor of epidermal growth factor receptor 1 & 2 (EGFR and HER2), enhanced PpIX fluorescence in a panel of GBM cell lines by blocking ABCG2 (ATP-binding cassette super-family G member 2)-mediated PpIX efflux, which suggests its potential for improving ALA for GBM surgery and PDT. Here we show that lapatinib enhanced PDT-induced cytotoxicity by promoting GBM cell death with the induction of apoptosis followed by necrosis. While the induction of tumor cell apoptosis was massive and rapid in the H4 cell line with no detectable Bcl-2 and a low level of Bcl-xL, it was delayed and much less in extent in A172, U-87 and U-118 cell lines with higher levels of pro-survival Bcl-2 family proteins. Lapatinib treatment alone neither reduced GBM cell viability nor had any significant effect on EGFR downstream signaling. Its enhancement of ALA-PDT was largely due to the increase of intracellular PpIX particularly in the mitochondria, resulting in the activation of mitochondria-mediated apoptosis in H4 cells. Our present study demonstrates that lapatinib inhibits ABCG2-mediated PpIX efflux and sensitizes GBM cells to ALA-PDT by inducing tumor cell death.

Detection of Muscular Metastasis in a Case of Parathyroid Carcinoma Using 18 F-FAPI-04 PET/CT.

ABSTRACT: A 46-year-old woman underwent surgery for parathyroid carcinoma 2 years ago. During follow-up, the patient presented with elevated parathyroid hormone (127.50 pg/mL; normal, 15-65). No abnormal uptake of 18 F-FDG or 11 C-choline was observed on 18 F-FDG and 11 C-choline PET/CT imaging. The patient was enrolled in a clinical trial for 18 F-FAPI PET/CT imaging, revealing a lesion with intense focal uptake within the left sternocleidomastoid muscle. The patient underwent surgery. Postoperative pathology and immunohistochemical analysis confirmed parathyroid carcinoma metastasis.

Preliminary Outcomes of Calcaneal Body Lengthening for the Calcaneus Shortening.

For lengthening irregular bones, such as calcaneus, there are few reports in the literature. This study aimed to introduce the treatment strategy and preliminary outcomes for calcaneus shortening using calcaneal body lengthening. From January 2017 to January 2022, calcaneal lengthening was conducted for three patients (two males and one female) who suffered from traumatic calcaneal shortening. The Achilles tendon was lengthened in one patient. After osteotomy of the calcaneus, an Ilizarov frame was used to gradually (1 mm/day) distract the calcaneal fragment. The lengthening procedure was stopped when the calcaneal height and length were restored based on radiography. The fixator was removed after bone union. The average follow-up length was 18 months (range, 14-24 months). X-ray was used for radiological assessments. Patients reported satisfaction using the 100-mm visual analog scale (VAS). Clinical outcome was evaluated following the American Orthopedic Foot and Ankle score. All data were assessed by two physicians blind to clinical assessments. The wound healed primarily in three cases. The bone got solid union without refracture and malunion. The distraction time was 30 days (range, 25-45 days). The fixation time was 113.3 days (average, 80-150 days). Calcaneal lengthening was 26 mm (range, 15-43 mm). The height and length of the calcaneus were restored nearly to the same as the opposite foot. The mean preoperative calcaneal pitch angle increased from 2.6 degrees to an average of 19.0 degrees after the surgery. The AOFAS score increased from 60.0 to 86.0. One patient experienced pin infection. The infection healed after changing the dressing. Calcaneal lengthening using an Ilizarov external fixator is a preferable technique to restore the length and height of the calcaneus and can achieve satisfactory foot function.