Time-Dependent Diffusion MRI Helps Predict Molecular Subtypes and Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer.

Background Time-dependent diffusion MRI has the potential to help characterize tumor cell properties; however, to the knowledge of the authors, its usefulness for breast cancer diagnosis and prognostic evaluation is unknown. Purpose To investigate the clinical value of time-dependent diffusion MRI-based microstructural mapping for noninvasive prediction of molecular subtypes and pathologic complete response (pCR) in participants with breast cancer. Materials and Methods Participants with invasive breast cancer who underwent pretreatment with time-dependent diffusion MRI between February 2021 and May 2023 were prospectively enrolled. Four microstructural parameters were estimated using the IMPULSED method (a form of time-dependent diffusion MRI), along with three apparent diffusion coefficient (ADC) measurements and a relative ADC diffusion-weighted imaging parameter. Multivariable logistic regression analysis was used to identify parameters associated with each molecular subtype and pCR. A predictive model based on associated parameters was constructed, and its performance was assessed using the area under the receiver operating characteristic curve (AUC) and compared by using the DeLong test. The time-dependent diffusion MRI parameters were validated based on correlation with pathologic measurements. Results The analysis included 408 participants with breast cancer (mean age, 51.9 years ± 9.1 [SD]). Of these, 221 participants were administered neoadjuvant chemotherapy and 54 (24.4%) achieved pCR. The time-dependent diffusion MRI parameters showed reasonable performance in helping to identify luminal A (AUC, 0.70), luminal B (AUC, 0.78), and triple-negative breast cancer (AUC, 0.72) subtypes and high performance for human epidermal growth factor receptor 2 (HER2)-enriched breast cancer (AUC, 0.85), outperforming ADC measurements (all P < .05). Progesterone receptor status (odds ratio [OR], 0.08; P = .02), HER2 status (OR, 3.36; P = .009), and the cellularity index (OR, 0.01; P = .02) were independently associated with the odds of achieving pCR. The combined model showed high performance for predicting pCR (AUC, 0.88), outperforming ADC measurements and the clinical-pathologic model (AUC, 0.73 and 0.79, respectively; P < .001). The time-dependent diffusion MRI-estimated parameters correlated well with the pathologic measurements (n = 100; r = 0.67-0.81; P < .001). Conclusion Time-dependent diffusion MRI-based microstructural mapping was an effective method for helping to predict molecular subtypes and pCR to neoadjuvant chemotherapy in participants with breast cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Partridge and Xu in this issue.

Effect of Cryogenic Treatment on Residual Stress and Microstructure of 6061 Aluminum Alloy and Optimization of Parameters.

Residual stress induced by solution treatment in 6061 aluminum alloy can lead to workpiece deformation, or even premature failure. The efficiency of traditional heat treatment for relieving residual stress is relatively low. Therefore, this study introduces a novel cryogenic treatment technique to reduce residual stress. The optimal cryogenic process parameters were achieved by orthogonal experiments: cryogenic temperature of 113 K, holding time of 24 h, 1 cryogenic cycle, and a cooling rate of 3 K·min-1, and the residual stress of aluminum alloy was measured by the blind hole method. The microstructural evolutions in 6061 aluminum alloy were tested by OM, SEM, and TEM. The results show that the introduction of cryogenic treatment can reduce residual stress in 6061 aluminum alloy by 64%, mainly due to the reduction of dislocations and the uniform distribution of ß'' phase.

CD200R1 immune checkpoint blockade by the first-in-human anti-CD200R1 antibody 23ME-00610: molecular mechanism and engineering of a surrogate antibody.

Human CD200R1 (hCD200R1), an immune inhibitory receptor expressed predominantly on T cells and myeloid cells, was identified as a promising immuno-oncology target by the 23andMe database. Blockade of CD200R1-dependent signaling enhances T cell-mediated antitumor activity in vitro and in vivo. 23ME-00610 is a potential first-in-class, humanized IgG1 investigational antibody that binds hCD200R1 with high affinity. We have previously shown that 23ME-00610 inhibits the hCD200R1 immune checkpoint function. Herein, we dissect the molecular mechanism of 23ME-00610 blockade of hCD200R1 by solving the crystal structure of 23ME-00610 Fab in complex with hCD200R1 and performing mutational studies, which show 23ME-00610 blocks the interaction between hCD200 and hCD200R1 through steric hindrance. However, 23ME-00610 does not bind CD200R1 of preclinical species such as cynomolgus monkey MfCD200R1. To enable preclinical toxicology studies of CD200R1 blockade in a pharmacologically relevant non-clinical species, we engineered a surrogate antibody with high affinity toward MfCD200R1. We used phage display libraries of 23ME-00610 variants with individual CDR residues randomized to all 20 amino acids, from which we identified mutations that switched on MfCD200R1 binding. Structural analysis suggests how the surrogate, named 23ME-00611, acquires the ortholog binding ability at the equivalent epitope of 23ME-00610. This engineering approach does not require a priori knowledge of structural and functional mapping of antibody-antigen interaction and thus is generally applicable for therapeutic antibody development when desired ortholog binding is lacking. These findings provide foundational insights as 23ME-00610 advances in clinical studies to gain understanding of the hCD200R1 immune checkpoint as a target in immuno-oncology.

Developing a rapid predictive model for falls in older hospitalized patients.

Background: This study was aimed to identify the independent risk factors for falls n hospitalized older patients and develop a corresponding predictive model. Methods: A retrospective observational study design was adopted, comprising 440 older patients with falls history and 510 older patients without falls history during hospitalization. Data collected included demographic information, vital signs, comorbidities, psychiatric disorder, function absent, current medication, other clinical indicators. Results: Mobility disability, high-risk medications use, frequency of hospitalizations, psychiatric disorder, visual impairment are independent risk factors for falls in older patients. The A-M2-HPV scoring system was developed. The AUC value of the nomogram was 0.884, indicating the model has excellent discriminative ability. The AUC value of the A-M2-HPV score was 0.788, demonstrating better discrimination and stratification capabilities. Conclusion: The A-M2-HPV scoring system provides a valuable tool to assess the risk of falls in hospitalized older patients and to aid in the implementation of preventive measures.

A 16-year evaluation of opportunistic lung cancer screening with low-dose CT in China: comparative findings between non-smokers and smokers.

BACKGROUND: Although low-dose computed tomography (LDCT) screening effectively reduces LC mortality in high-risk individuals with a history of smoking in China, the feasibility and efficacy of lung cancer screening (LCS) in individuals who never smoked versus individuals who smoked remains unclear. METHODS: We conducted a retrospective analysis of prospective cohort studies at the National Cancer Center (NCC) in China from January 2006 to December 2022. A comprehensive LCS initiative was undertaken, involving 30,468 participants (54.5% male). Participants underwent LCS using LDCT. Potential malignancies were managed through joint consensus between patients and their physicians. Epidemiology, screening eligibility criteria, and LC detection rates and survival outcomes were compared between individuals who smoked and individuals who never smoked. RESULTS: Among 30,468 participants, 339 LCs were pathologically confirmed in 289 patients. The LC detection rate was 0.9% (289/30,468) overall, 0.8% in individuals who smoked (71/9,042), and 1.0% in individuals who never smoked (218/21,426). In individuals who smoked, LC detection rates were 0.5% (21/4516) and 1.1% (50/4526) in the < 20 and ≥ 20 pack-year subgroups, respectively (P = 0.001). Early-stage LC (stage 0 or I) was detected in 73.8% of the individuals who smoked and in 78.8% of individuals who never smoked, while advanced LC (stage III-IV) was found 8.8% of individuals who smoked and 4.2% of individuals who never smoked, respectively. Significant differences in histologic types were found between individuals who smoked and individuals who never smoked (P = 0.01), although adenocarcinoma was the most prevalent in both groups, at 83.0% and 78.8%, respectively. The median nodule size was 9.9 mm (IQR, 8.0-13.8) in individuals who smoked and 9.2 mm (IQR, 6.8-13.6) in individuals who never smoked (P = 0.228). Individuals who never smoked tended to favour surgical treatment alone (88.0%) more than individuals who smoked (81.3%). The 10-year survival rate was higher in individuals who never smoked (92.6%) than in individuals who smoked (88.8%). Only 15.6% (45/289) of patients with LC met the United States Preventive Services Task Force (USPSTF) criteria for LDCT eligibility, while 29.0% (84/289) met the China guideline for the screening and early detection of lung cancer (CGSL) criteria. Median follow-up for those followed was 25.4 (IQR, 13.7-43.3) months. CONCLUSIONS: LDCT screening improves early LC detection and treatment outcomes for both individuals who smoked and individuals who never smoked. Significant differences exist in epidemiology, histologic type, and survival between these groups. The USPSTF and CGSL criteria miss a significant number of LC cases, particularly among individuals who never smoked. Integrating individuals who never smoked into LCS programs is essential, yet it comes with its own challenges, such as managing radiation risks, allocating resources effectively, and considering financial aspects. Consequently, there is an urgent need for LCS programs in China to better identify the "high-risk" non-smoker population susceptible to LC and to ensure that potential risks associated with screening are reduced.

Anticancer effects of tanshinone IIA in bladder urothelial carcinoma by down-regulating aurora A, HIF-1α and Bcl-2 both in vitro and in vivo.

The mechanisms of the anticancer effect of Tanshinone IIA (Tan IIA) on Bladder urothelial carcinoma (BUC) remain mostly unknown. In this study, BUC T24 cells were treated with Tan IIA at different concentrations and durations. The apoptosis, proliferation and invasion of T24 cells were evaluated using MTT assays, Annexin V-FITC Staining, Hoechst staining and Trans well assay. One group of T-24 cell xenograft mice was treated with Tan IIA, while the other group received normal saline for 25 days. Subsequently, the size of tumors as well as mRNA and protein expression of Aurora A, HIF-1α and Bcl-2 were measured both in vitro and in vivo. Tan IIA induced apoptosis, inhibited proliferation, suppressed invasion of T24 cells in a time- and dose-dependent manner in vitro and attenuated growth in vivo. The decreasing of mRNA and protein expression of Aurora A, HIF-1α and Bcl-2 in T-24 cells treated with Tan IIA were detected in a time- and dose-dependent manner both in vitro and in vivo. The pro-apoptotic, anti-proliferative and anti-invasive effects of Tan IIA on T-24 cells may be derived from inhibition of mRNA and protein expression of Aurora A, HIF-1α and Bcl-2. Tan IIA could potentially serve as a novel potential anti-cancer agent for BUC.

Evaluation of peripheral blood inflammation indexes as prognostic markers for colorectal cancer metastasis.

The aim of this study was to evaluate the prognostic value of peripheral blood inflammation indexes in patients with metastatic Colorectal Cancer (CRC) and to establish a predictive scoring system. A total of 324 CRC patients diagnosed through pathological examination from January 2017 to July 2022 at the Third Affiliated Hospital of Kunming Medical University were included. The prognosis of patients with metastatic CRC was examined, and the correlation between IL-10 expression in pathological tissues and IL-10 expression in serum was analyzed. The results showed that the prognosis of CRC was poorer when metastasis occurred (P < 0.001). Additionally, IL-10 was highly expressed in the metastatic CRC group (P = 0.018), and the expression of IL-10 in pathological tissues of patients with metastatic CRC was positively correlated with the expression of IL-10 in serum (P = 0.037). The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-white blood cell ratio (LWR), aggregate index of systemic inflammation (AISI), monocyte-to-lymphocyte ratio (MLR), systemic inflammatory response index (SIRI), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and interleukin-10 (IL-10) were calculated and determined by ROC curve. The critical values were 2.135, 3.735, 353.745, 0.265, 1.025, 52.975, 353.635, and 11.25, respectively. Inflammatory indexes with an AUC of more than 0.6 were selected, and each colorectal cancer patient with any of these risk factors was assigned a score of one. The 324 patients were then divided into two groups: 0-4 for the low-risk group and 4-8 for the high-risk group. The occurrence of distant metastases in the two groups was statistically analyzed. The results showed that the OS and PFS of the low-risk group were significantly superior to those of the high-risk group (P < 0.05). These findings indicate that NLR, LWR, AISI, MLR, SIRI, PNI, ALI, and IL-10 are risk factors for distant metastasis in CRC patients. Therefore, the prediction scores of these indexes can be used to effectively evaluate the prognosis of patients with metastatic CRC.

Inter-observer consistency on subsolid nodule follow-up recommendation based on National Comprehensive Cancer Network (NCCN) guidelines in low-dose computed tomography (LDCT) lung cancer screening.

Background: Follow-up management of pulmonary nodules is a crucial component of lung cancer screening. Consistency in follow-up recommendations is essential for effective lung cancer screening. This study aimed to assess inter-observer agreement on National Comprehensive Cancer Network (NCCN) guideline-based follow-up recommendation for subsolid nodules from low-dose computed tomography (LDCT) screening. Methods: A retrospective collection of LDCT reports from 2014 to 2017 for lung cancer screening was conducted using the Radiology Information System and keyword searches, focusing on subsolid nodules. A total of 110 LDCT cases containing subsolid nodules were identified. Two senior radiologists provided standardized follow-up recommendation. Follow-up recommendation was categorized into four groups (0-, 3-, 6-, and 12-month). To ensure overall balance and representativeness of the follow-up categories, 60 scans from 60 participants were included (distribution ratio 1:1:2:2). Cases were categorised into follow-up recommendation groups by five observers following NCCN guidelines. Fleiss' kappa statistic was used to evaluate inter-observer agreement. Results: Overall accuracy rate for follow-up recommendation among five observers was 72.3%. Chest radiologists' overall agreement was significantly higher than radiology residents (P<0.01). The overall agreement among the five observers was moderate, with a Fleiss' kappa of 0.437. For all paired readers, the mean Cohen's kappa value was 0.603, with 95% confidence interval (CI) from 0.489 to 0.716. Chest radiologists demonstrated substantial agreement, evidenced by a Cohen's kappa of 0.655 (95% CI: 0.503-0.807). In contrast, the mean Cohen's kappa among radiology residents was 0.533 (95% CI: 0.501-0.565). The majority of cases with discrepancies, accounting for 73.5%, were associated with the same risk-dominant nodules. A higher proportion of part-solid nodule was a risk factor for discrepancies. Of the 600 paired readings, major discrepancies and substantial discrepancies were observed in 27.5% and 4.8% (29/600) of the cases. Conclusions: In subsolid nodules, category evaluation of observer follow-up recommendation based on NCCN guidelines achieved moderate consistency. Disagreements were mainly caused by measurement and type disagreements of identical risk-dominant nodules. Part-solid nodule was a contributor for discrepancies in follow-up recommendation. Major and substantial management discrepancies were 27.5% and 4.8% in the paired evaluations.

Type 2 hypersensitivity disorders, including systemic lupus erythematosus, Sjögren's syndrome, Graves' disease, myasthenia gravis, immune thrombocytopenia, autoimmune hemolytic anemia, dermatomyositis, and graft-versus-host disease, are THαß-dominant autoimmune diseases.

The THαß host immunological pathway contributes to the response to infectious particles (viruses and prions). Furthermore, there is increasing evidence for associations between autoimmune diseases, and particularly type 2 hypersensitivity disorders, and the THαß immune response. For example, patients with systemic lupus erythematosus often produce anti-double stranded DNA antibodies and anti-nuclear antibodies and show elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 throughout the disease course. These cytokines and antibody isotypes are associated with the THαß host immunological pathway. Similarly, the type 2 hypersensitivity disorders myasthenia gravis, Graves' disease, graft-versus-host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjögren's syndrome have also been linked to the THαß pathway. Considering the potential associations between these diseases and dysregulated THαß immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferon α/ß could be explored for effective management.

Pelvic congestion syndrome analysis through quantitative 2-dimensional phase-contrast magnetic resonance imaging: A promising vision from an observational cohort study.

BACKGROUND: To examine the application of quantitative 2-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) for treating patients with pelvic congestion syndrome (PCS). MATERIALS AND METHODS: We conducted a retrospective cross-sectional analysis by using quantitative 2D PC-MRI data enrolled between April 2017 and Sep 2023. In addition, 32 healthy female controls (HCs) were included. RESULTS: Most patients with PCS presented with chronic pelvic pain and more than half had extra-pelvic venous symptoms (80/81, 98% and 45/81, 56%, respectively). Quantitative 2D PC-MRI analyzed the 81 patients with PCS, 239 patients without PCS, and 32 HCs. The patients with PCS had higher stroke volume (SV), absolute SV (ASV), and mean flux (MF) in the calf region (interstitial pixel shift) than did the HCs. In the left gonadal vein, the patients with PCS had higher SV, backward flow volume (BFV), ASV, and MF and lower forward flow volume (FFV), stroke distance (SD), and mean velocity (MV) than did the HCs. However, the patients with PCS had lower SV, FFV, MF, SD, and MV in the great saphenous veins. Quantitative 2D PC-MRI analysis revealed that the PCS group had higher SV, FFV, BFV, ASV, and MF in the calf region than did the non-PCS group. The variables that most strongly differentiated the patients with PCS from the HCs were SV in the great saphenous veins, SD in the great saphenous veins and left gonadal vein, and MV in the great saphenous veins and left gonadal vein. Caudal flow in the left gonadal vein was identified in half of the patients with PCS (39/81, 48.1%); 14 of them received embolization for left gonadal vein. CONCLUSIONS: In additional to providing an objective 3-dimensional morphology of the pelvic veins and extra-pelvic leaks, quantitative 2D PC-MRI analysis reveals distinct hemodynamic profiles between patients with PCS, those without PCS, and HCs, especially in the gonadal veins and regional perfusion of the calves.

ARHGEF39 targeted by E2F1 fosters hepatocellular carcinoma metastasis by mediating fatty acid metabolism.

BACKGROUND: Hepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer. Previous studies have implicated ARHGEF39 in various cancer progression processes, but its impact on HCC metastasis remains unclear. METHODS: Bioinformatics analysis and qRT-PCR were employed to test ARHGEF39 expression in HCC tissues and cells, identified enriched pathways associated with ARHGEF39, and investigated its regulatory relationship with E2F1. The impact of ARHGEF39 overexpression or knockdown on cellular phenotypes in HCC was assessed through the implementation of CCK-8 and Transwell assays. Accumulation of neutral lipids was determined by BODIPY 493/503 staining, while levels of triglycerides and phospholipids were measured using specific assay kits. Expression of E-cadherin, Vimentin, MMP-2, MMP-9, and FASN were analyzed by Western blot. The interaction between ARHGEF39 and E2F1 was validated through ChIP and dual-luciferase reporter assays. RESULTS: Our study demonstrated upregulated expression of both ARHGEF39 and E2F1 in HCC, with ARHGEF39 being associated with fatty acid metabolism (FAM) pathways. Additionally, ARHGEF39 was identified as a downstream target gene of E2F1. Cell-based experiments unmasked that high expression of ARHGEF39 mediated the promotion of HCC cell viability, migration, and invasion via enhanced FAM. Moreover, rescue assays demonstrated that the promotion of HCC cell metastasis by high ARHGEF39 expression was attenuated upon treatment with Orlistat. Conversely, the knockdown of E2F1 suppressed HCC cell metastasis and FAM, while the upregulation of ARHGEF39 counteracted the repressive effects of E2F1 downregulation on the metastatic potential of HCC cells. CONCLUSION: Our findings confirmed the critical role of ARHGEF39 in HCC metastasis and unmasked potential molecular mechanisms through which ARHGEF39 fostered HCC metastasis via FAM, providing a theoretical basis for exploring novel molecular markers and preventive strategies for HCC metastasis.

An endogenous oxygen self-supplied nanoplatform with GSH-depleted and NIR-II triggered electron-hole separation for enhanced photocatalytic anti-tumor therapy.

The use of artificial enzymes and light energy in photocatalytic therapy, a developing drug-free therapeutic approach, can treat malignant tumors in vivo. However, the relatively deficient oxygen concentration in the tumor microenvironment (TME) restrains their further tumor treatment capability. Herein, a novel nanoplatform with Cu7S4@Au nanocatalyst coated by MnO2 was successfully designed. After 1064 nm light irradiation, the designed nanocatalyst can promote the separation of light generated electron-hole pairs, resulting in ROS generation and tumor cell apoptosis. The MnO2 shelled nanoplatform can function as a TME-responsive oxygen self-supplied producer to improve photocatalyst treatment and GSH depletion. In summary, the designed novel nanoplatform shows efficient inhibition of tumor growth via GSH depletion and synergistic photocatalytic therapy, which is of great significance for improving the clinical tumor treatment effect.

KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Promising response of proliferative glomerulonephritis with monoclonal IgG deposits to low-dose daratumumab: a case report.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare disease without standardized treatment modalities. Daratumumab is a human IgG monoclonal anti-CD38 antibody that has been demonstrated to be highly effective and safe in the treatment of PGNMID. This article reports a 66-year-old female who suffered from edema in both lower limbs and face for 6 years with mild proteinuria and hypoproteinemia. Renal biopsy displayed eight glomeruli, among which two presented with glomerulosclerosis, and the remaining six exhibited moderate diffuse hyperplasia of glomerular mesangial cells and stroma with endothelial cell proliferation. Immunofluorescence microscopy revealed lumpy and diffuse deposits of C3, C1q, IgG, and κ light chain in the glomerular mesangium, with strongly positive staining for IgG3 and varying degrees of weak to negative staining for IgG1, IgG2, IgG4, and λ light chain. Additionally, ultrastructural analysis unveiled that the glomerular basement membrane was segmentally thickened, accompanied by diffuse pedicle fusion, segmental tethered insertion, subendothelial deposits, and electron-dense material in tethered areas. The patient received a total dose of 800 mg of daratumumab (400 mg daily for two consecutive days), as well as daily prednisone (25 mg) and valsartan (80 mg), for treatment and achieved complete remission after three-month follow-up. This case represents an early attempt to treat PGNMID with low-dose daratumumab but requires long-term follow-up.

ROS-Responsive Nanoprobes for Bimodal Imaging-Guided Cancer Targeted Combinatorial Therapy.

Purpose: Chemotherapy mediated by Reactive oxygen species (ROS)-responsive drug delivery systems can potentially mitigate the toxic side effects of chemotherapeutic drugs and significantly enhance their therapeutic efficacy. However, achieving precise targeted drug delivery and real-time control of ROS-responsive drug release at tumor sites remains a formidable challenge. Therefore, this study aimed to describe a ROS-responsive drug delivery system with specific tumor targeting capabilities for mitigating chemotherapy-induced toxicity while enhancing therapeutic efficacy under guidance of Fluorescence (FL) and Magnetic resonance (MR) bimodal imaging. Methods: Indocyanine green (ICG), Doxorubicin (DOX) prodrug pB-DOX and Superparamagnetic iron oxide (SPIO, Fe3O4) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) by double emulsification method to prepare ICG/ pB-DOX/ Fe3O4/ PLGA nanoparticles (IBFP NPs). The surface of IBFP NPs was functionalized with mammaglobin antibodies (mAbs) by carbodiimide method to construct the breast cancer-targeting mAbs/ IBFP NPs (MIBFP NPs). Thereafter, FL and MR bimodal imaging ability of MIBFP NPs was evaluated in vitro and in vivo. Finally, the combined photodynamic therapy (PDT) and chemotherapy efficacy evaluation based on MIBFP NPs was studied. Results: The multifunctional MIBFP NPs exhibited significant targeting efficacy for breast cancer. FL and MR bimodal imaging clearly displayed the distribution of the targeting MIBFP NPs in vivo. Upon near-infrared laser irradiation, the MIBFP NPs loaded with ICG effectively generated ROS for PDT, enabling precise tumor ablation. Simultaneously, it triggered activation of the pB-DOX by cleaving its sensitive moiety, thereby restoring DOX activity and achieving ROS-responsive targeted chemotherapy. Furthermore, the MIBFP NPs combined PDT and chemotherapy to enhance the efficiency of tumor ablation under guidance of bimodal imaging. Conclusion: MIBFP NPs constitute a novel dual-modality imaging-guided drug delivery system for targeted breast cancer therapy and offer precise and controlled combined treatment options.

Ginsenoside Rg1 protects the blood-brain barrier and myelin sheath to prevent postoperative cognitive dysfunction in aged mice.

In this study, the postoperative cognitive dysfunction (POCD) mouse model was established to observe the changes in inflammation, blood-brain barrier permeability, and myelin sheath, and we explore the effect of ginsenoside Rg1 pretreatment on improving POCD syndrome. The POCD model of 15- to 18-month-old mice was carried out with internal fixation of tibial fractures under isoflurane anesthesia. Pretreatment was performed by continuous intraperitoneal injection of ginsenoside Rg1(40 mg/kg/day) for 14 days before surgery. The cognitive function was detected by the Morris water maze. The contents of interleukin-1ß and tumor necrosis factor-α in the hippocampus, cortex, and serum were detected by ELISA. The permeability of blood-brain barrier was observed by Evans blue. The mRNA levels and protein expression levels of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin basic protein (MBP), beta-catenin, and cyclin D1 in the hippocampus were analyzed by quantitative PCR and western blotting. The protein expression levels of ZO-1 and Wnt1 in the hippocampus were analyzed by western blotting. Finally, the localizations of CNPase and MBP in the hippocampus were detected by immunofluorescence. Ginsenoside Rg1 can prevent POCD, peripheral and central inflammation, and blood-brain barrier leakage, and reverse the downregulation of ZO-1, CNPase, MBP, and Wnt pathway-related molecules in aged mice. Preclinical studies suggest that ginsenoside Rg1 improves postoperative cognitive function in aged mice by protecting the blood-brain barrier and myelin sheath, and its specific mechanism may be related to the Wnt/ß-catenin pathway.

Targeted agents plus CHOP compared with CHOP as the first-line treatment for newly diagnosed patients with peripheral T-cell lymphoma (GUIDANCE-03): an open-label, multicentre phase 2 clinical trial.

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p = 0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).

Multifunctional Roles of Zinc in Cadmium Transport in Soil-Rice Systems: Novel Insights from Stable Isotope Fractionation and Gene Expression.

The effect of Zn on Cd accumulation in rice varies under flooding and drainage conditions, and the underlying mechanism during uptake and transport from the soil to grains remains unclear. Isotope fractionation and gene expression were investigated using pot experiments under distinct water regimes and with Zn addition to gain a deeper understanding of the molecular effects of Zn on Cd uptake and transport in rice. The higher OsHMA2 expression but constitutively lower expression of zinc-regulated, iron-regulated transporter-like protein (ZIP) family genes in roots under the drainage regime than the flooding regime caused the enrichment of nonheavy Zn isotopes in the shoots relative to roots but minimally affected Cd isotopic fractionation. Drainage regime seem to exert a striking effect on the root-to-shoot translocation of Zn rather than Cd, and increased Zn transport via OsHMA2. The changes in expression patterns in response to Zn addition were similar to those observed upon switching from the flooding to drainage regime, except for OsNRAMP1 and OsNRAMP5. However, soil solution-to-rice plants and root-to-shoot fractionation toward light Zn isotopes with Zn addition (Δ66Znrice plant-soil solution = -0.49 to -0.40‰, Δ66Znshoot-root = -0.36 to -0.27‰) indicated that Zn transport occurred via nonspecific uptake pathways and OsHMA2, respectively. Accordingly, the less pronounced and minimally varied Cd isotope fractionation suggested that OsNRAMP5 and OsHMA2 are crucial for Cd uptake and root-to-shoot transport, respectively, facilitating Cd accumulation in grains. This study demonstrated that a high Zn supply promotes Cd uptake and root-to-shoot transport in rice by sharing distinct pathways, and by utilizing a non-Zn-sensitive pathway with a high affinity for Cd.

Migraine and gastroesophageal reflux disease: Disentangling the complex connection with depression as a mediator.

OBJECTIVE: Gastroesophageal reflux disease (GERD) and migraine are public health concerns worldwide. No observational study has conclusively elucidated the causal relationship between these two conditions. We employed Mendelian randomization (MR) methods to explore the potential causal links between GERD and migraine. METHODS: Genome-wide association studies were subjected to MR to infer the causality between GERD and migraine. Bidirectional two-sample MR was performed to establish causal relationships. Multivariable MR analysis was conducted to adjust potential confounding factors, and mediation MR analysis was utilized to assess the role of depression between GERD and migraine as a mediator. We primarily utilized the inverse variance weighted method (IVW) and sensitivity analysis methods, including MR-Egger, weighted median, and leave-one-out methods. We assessed heterogeneity and pleiotropy to ensure the reliability of the results. RESULTS: Bidirectional two-sample MR revealed a positive causal effect of GERD on migraine (IVW: OR = 1.49, 95% CI: 1.34-1.66, p = 3.70E-13). Migraine did not increase the risk of GERD (IVW: OR = 1.07, 95% CI: 0.98-1.17, p = 0.1139). Multivariable MR indicated that the positive causal effect of GERD on migraine remained after adjustment for factors, such as smoking, alcohol consumption, obesity, type 2 diabetes, and depression. Mediation MR revealed that depression mediated 28.72% of GERD's effect on migraine. MR analysis was supported by all sensitivity analyses and was replicated and validated in another independent dataset on migraine. CONCLUSION: Our findings elucidate the positive causal effect of GERD on migraine and underscores the mediating role of depression in increasing the risk of migraine due to GERD. Effective control of GERD, particularly interventions targeting depression, may aid in preventing the occurrence of migraine. Future research should delve deeper into the specific pathophysiological mechanisms through which GERD affects migraine risk, facilitating the development of more effective drug targets or disease management strategies.

Epidemiology, Treatment Patterns, and Healthcare Resource Utilization Study of Patients With Alopecia Areata in Taiwan's National Health Insurance Research Database.

OBJECTIVES: This study investigated the epidemiology, treatment patterns, and resource utilization in patients with alopecia areata (AA) in Taiwan using the National Health Insurance Research Database. AA severity was determined by treatment use and diagnostic codes in the year after enrollment (including corticosteroids, systemic immunosuppressants, topical immunotherapy, and phototherapy). METHODS: The cross-sectional analysis was conducted to estimate the incidence and prevalence of AA from 2016 to 2020. For the longitudinal analysis, 2 cohorts were identified: mild/moderate and severe. The cohorts were matched based on age, gender, and comorbidities. Patients were enrolled upon their first claim with an AA diagnosis during the index period of 2017-2018. RESULTS: The number of patients with AA increased from 3221 in 2016 to 3855 in 2020. The longitudinal analysis identified 1808 mild/moderate patients and 452 severe patients. Mild/moderate patients used higher levels of topical corticosteroids (82.41%) than severe patients (73.45%). Conversely, severe patients used more topical nonsteroids (41.81%) and systemic therapies (51.77%) than mild/moderate patients (0.44% and 16.15%, respectively). Oral glucocorticoids use was higher in severe patients (47.57%) relative to mild/moderate patients (14.88%), whereas the use of injectable forms was similar. The most used systemic immunosuppressants were methotrexate, cyclosporin, and azathioprine. Topical immunotherapy utilization decreased with subsequent treatment lines for severe patients. Treatment persistence at 6 months was low for all treatments. Severe patients had higher annual AA-related outpatient visits than the mild/moderate cohort. CONCLUSIONS: These findings highlight the need for additional innovations and therapies to address the clinical and economic burden of AA.