CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has transformed cancer immunotherapy. However, significant challenges limit its application beyond B cell-driven malignancies, including limited clinical efficacy, high toxicity, and complex autologous cell product manufacturing. Despite efforts to improve CAR T cell therapy outcomes, there is a growing interest in utilizing alternative immune cells to develop CAR cells. These immune cells offer several advantages, such as major histocompatibility complex (MHC)-independent function, tumor microenvironment (TME) modulation, and increased tissue infiltration capabilities. Currently, CAR products from various T cell subtypes, innate immune cells, hematopoietic progenitor cells, and even exosomes are being explored. These CAR products often show enhanced antitumor efficacy, diminished toxicity, and superior tumor penetration. With these benefits in mind, numerous clinical trials are underway to access the potential of these innovative CAR cells. This review aims to thoroughly examine the advantages, challenges, and existing insights on these new CAR products in cancer treatment.

Synthesis and Evaluation of [18F]AlF-NOTA-c-DVAP: A Novel PET Probe for Imaging GRP78 in Cancer.

GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe's performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe's binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20-50 GBq/µmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of -3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.

Synthesis and preclinical evaluation of a novel PET/fluorescence dual-modality probe targeting fibroblast activation protein.

Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [68Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [68Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation.

Effects of Breast-Conserving Surgery and Mastectomy on the Survival of Patients with Early-Stage (T1-2N0-1M0) HER2-Positive Breast Cancer: A Propensity Score-Matched Analysis.

INTRODUCTION: Although breast-conserving therapy (BCT) promises at least a similar survival rate for patients with early breast cancer compared with mastectomy, its efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors remains unclear. Therefore, we conducted this study to explore differential effects of BCT and mastectomy on survival outcomes of patients with early-stage HER2-positive breast cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and basic characteristics of patients who received either BCT or mastectomy were balanced using propensity score matching (PSM). Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards regression were performed. RESULTS: In total, 20,277 patients were diagnosed with T1-2N0-1M0 HER2-positive breast cancer between 2010 and 2015. After PSM, 6,185 pairs of patients were enrolled for further analysis. Compared with those undergoing mastectomy, patients receiving BCT had superior overall survival (OS) (hazard ratio [HR], 0.63; 95% confidence interval [CI]: 0.55-0.73; p < 0.001) and breast cancer-specific survival (BCSS) (HR: 0.59; 95% CI: 0.48-0.71; p < 0.001). The subgroup analyses revealed that survival outcomes (OS and BCSS) of BCT were better than those of mastectomy among estrogen receptor (ER)+/progesterone receptor (PR)+/HER2+, ER+/PR-/HER2+, and ER-/PR-/HER2+ subtypes (p < 0.05 for all); however, patients with ER-/PR+/HER2+ subtypes who underwent BCT had similar OS and BCSS (p > 0.05 for both) to those treated with mastectomy. DISCUSSION/CONCLUSION: Despite the aggressiveness of the disease, we found that BCT may confer better long-term survival than mastectomy for patients with T1-2N0-1M0 HER2-positive breast cancer, particularly for those with ER+/PR+/HER2+, ER+/PR-/HER2+, and ER-/PR-/HER2+ subtypes. In addition, our study provided insights into the clinical applications of BCT. However, this retrospective study has introduced several inevitable limitations, and further prospective research is warranted to verify these conclusions.

Clinical experience of bench surgery combined with autotransplantation after three-dimensional laparoscopic nephrectomy for the treatment of highly complex renal tumor.

OBJECTIVE: To assess the feasibility and safety of three-dimensional (3D) laparoscopic nephrectomy in combination with bench surgery and autotransplantation for treating highly complex renal tumors. MATERIALS AND METHODS: The clinical data of six patients with highly complex renal cell carcinoma were collected. All patients underwent 3D laparoscopic nephrectomy in combination with bench surgery and autotransplantation by the same surgeons, two of them had previously undergone laparoscopic partial nephrectomy for contralateral renal cancer. RESULTS: The total operative time was 366 ± 65 min, the warm ischemia time (WIT) was 1.3 ± 0.4 min, and the cold ischemia time was 121 ± 26 min. While one patient received a diluted autologous blood transfusion, the intraoperative blood loss was 217 ± 194 ml. No increase in the serum creatinine (SCr) level was observed at postoperative day 30 compared with the preoperative time, and none of the patients received dialysis either during the hospital stay or to date. Although one patient underwent nephrectomy due to tumor recurrence in the transplanted kidney, the others reported no tumor recurrence or distant metastases on imaging to date. CONCLUSION: 3D laparoscopic nephrectomy, when combined with bench surgery and autotransplantation, can become a feasible option for treating highly complex renal cell carcinoma cases when expecting to preserve renal function maximally.

Radiosynthesis, preclinical evaluation and pilot clinical PET imaging study of a 18F-labeled tracer targeting fibroblast activation protein.

Fibroblast activation protein (FAP) is a promising molecular target for imaging in various types of cancers. Several 18F-labeled FAP inhibitor (FAPI) tracers have been evaluated in clinical study. However, these tracers display high physiological uptake in gallbladder and bile duct system. To overcome the limitation, we herein designed a novel radiotracer named 18F-FAPTG. 18F-FAPTG was produced with a non-decay-corrected radiochemical yield of 24.0 ± 6.0% and 22.0 ± 7.0% for manual and automatic synthesis, respectively. 18F-FAPTG exhibited high hydrophilicity and stability in vitro. The studies of cellular uptake, internalization, efflux properties and competitive binding to FAP of 18F-FAPTG indicated that the tracer showed high specificity, rapid internalization and low cellular efflux in FAP-positive cells. Biodistribution studies and microPET in mice bearing FAP-positive xenografts demonstrated extremely low uptake in the majority of other organs and main excretion of 18F-FAPTG through the urinary system. Furthermore, compared to 18F-FAPI-42, 18F-FAPTG showed significantly lower uptake in gallbladder, higher tumor uptake and longer tumor retention. In the pilot clinical study, 18F-FAPTG PET/CT demonstrated favorable tumor-to-background ratios in most organs and clearly displayed the malignant lesions. Our findings indicated that 18F-FAPTG had an advantage over 18F-FAPI-42 in PET imaging for cancers located in gallbladder the bile duct system. Thus, 18F-FAPTG could be an alternative to the currently available FAPI tracers.

Noninvasive imaging of FAP expression using positron emission tomography: A comparative evaluation of a [18F]-labeled glycopeptide-containing FAPI with [18F]FAPI-42.

PURPOSE: Research on fibroblast activating protein (FAP)-targeting inhibitor (FAPI) has become an important focus for cancer imaging and radiotherapy. Quinoline-based tracers [68 Ga]FAPI-04 and [18F]FAPI-42 have been widely used for positron emission tomography (PET) imaging of most tumors. However, there exist some limitations of these tracers with high uptake in biliary duct system and unstable uptake in pancreas, unsuitable for abdominal tumors PET imaging. Here we developed a [18F]-labeled glycopeptide-containing FAPI tracer (named [18F]FAPT) for PET imaging of FAP in cancers. METHODS: [18F]FAPT was synthesized manually and automatically. The competitive binding to FAP, cellular internalization, and efflux characteristics were examined in vitro using A549-FAP cells. Dynamic MicroPET and biodistribution studies of [18F]FAPT were then conducted in A549-FAP and U87MG xenograft tumor mouse models compared with [18F]FAPI-42. Five healthy volunteers and three patients with cancer underwent [18F]FAPT PET/CT. RESULTS: Preclinical and clinical studies showed specific binding of [18F]FAPT to FAP and favorable pharmacokinetic properties with better hydrophilicity, lower uptake in biliary duct system, higher tumor uptake and longer tumor retention compared with [18F]FAPI-42. The biodistribution of [18F]FAPT in healthy volunteers and patients with cancer displayed low uptake in most normal tissues except for pancreas, thyroid and salivary gland, which could contribute to high tumor-to-background ratios in most cancers. CONCLUSION: [18F]FAPT is better PET tracer than [18F]FAPI-42 for imaging of biliary duct system cancer, potentially providing a tool to examine FAP expression in most cancers with high tumor-to-background ratios.

A Comparative Study of 18F-FAPI-42 and 18F-FDG PET/CT for Evaluating Acute Kidney Injury in Cancer Patients.

PURPOSE: Compare the value of imaging using positron 18F-labeled fibroblast activation protein inhibitor-42 (18F-FAPI-42) and 18F-labeled deoxyglucose (18F-FDG) for assessment of AKI. PROCEDURES: This study analyzed cancer patients who received 18F-FAPI-42 and 18F-FDG PET/CT imaging. Eight patients had AKI with bilateral ureteral obstruction (BUO), eight had BUO (CKD1-2) with no acute kidney disease (AKD), and eight had no ureteral obstruction (UO) with normal renal function. The average standardized uptake value (SUVave) of the renal parenchyma (RP-SUVave), the blood pool SUVave (B- SUVave), SUVave in the highest region of the renal collective system (RCS-SUVave), and the highest serum creatinine level (top SCr) were recorded. RESULTS: The 18F-FAPI-42 and 18F-FDG results showed that radiotracer of renal parenchyma was more concentrated in the AKI group than in the other two groups, whereas the RP-SUVave from 18F-FAPI-42 was higher than that from 18F-FDG in the AKI group (all P < 0.05). 18F-FAPI-42 imaging in the AKI group showed uptake by the renal parenchyma with a diffuse increase, but very little radiotracer in the renal collecting system, similar to a "super kidney scan." The renal parenchyma also had an increase of SUVave, with accumulation of radiotracer in the renal collecting system. AKI was more severe when a patient had a "super kidney scan" in both kidneys (P < 0.05). The B-SUVave level was higher in the AKI group than in the other two groups in 18F-FAPI-42 (both P < 0.05). CONCLUSIONS: 18F-FAPI-42 imaging had higher RP-SUVave than 18F-FDG imaging in cancer patients who had BUO with AKI. An increased renal parenchyma uptake in both kidneys and low radiotracer distribution in the collecting system suggest more severe AKI.

Pharmacokinetic analysis of 6-O-[18F]FEE for PET imaging of EGFR mutation.

6-O-[18F]Fluoroethylerlotinib (6-O-[18F]FEE), with a suitable half-life for commercial distribution, may be a good replacement for [11C]erlotinib to identify epidermal growth factor receptor (EGFR) positive tumors with activating mutations to tyrosine kinase inhibitors therapy. In this study, we explored the fully automated synthesis of 6-O-[18F]FEE and investigated its pharmacokinetics in tumor-bearing mice. 6-O-[18F]FEE with high specific activity (28-100 GBq/µmol) and radiochemistry purity (over 99 %) was obtained by two-step reaction and Radio-HPLC separation in PET-MF-2 V-IT-1 automated synthesizer. PET imaging of 6-O-[18F]FEE in HCC827, A431, and U87 tumor-bearing mice with different EGFR expression and mutation was performed. Uptake and blocking of PET imaging indicated that the probe specifically targeted exon 19 deleted EGFR (the quantitative analysis of tumor-to-mouse ratio for HCC827, HCC827 blocking, U87, A431 was 2.58 ± 0.24, 1.20 ± 0.15, 1.18 ± 0.19, and 1.05 ± 0.13 respectively). Dynamic imaging was used to study the pharmacokinetics of the probe in tumor-bearing mice. Logan plot graphical analysis demonstrated late linearity and a high fitting correlation coefficient (0.998), supporting reversible kinetics. According to the Akaike Information Criterion (AIC) rule, the 2-compartment reversible model was more consistent with the metabolic properties of 6-O-[18F]FEE. The automated radiosynthesis and pharmacokinetic analysis will promote clinically transformation of 6-O-[18F]FEE.

Microbial Biomarkers for Lung Cancer: Current Understandings and Limitations.

As our "hidden organ", microbes widely co-exist at various sites on the human body. These microbes are collectively referred to as the microbiome. A considerable number of studies have already proven that the microbiome has significant impacts on human health and disease progression, including cancers. The recent discovery of cancer-specific microbiomes renders these cancer-associated microbes as potential biomarkers and therapeutic targets. While at low biomass levels, the lung microbiome still dramatically influences the initiation, progression and treatment of lung cancers. However, research on lung cancer-associated microbiomes is emerging, and most profiling studies are performed within three years. Unfortunately, there are substantial inconsistencies across these studies. Variations in microbial diversity were observed, and different microbial biomarkers for lung cancer have been proposed. In this review, we summarized the current findings of lung cancer microbiome studies and attempt to explain the potential reasons for the dissimilarities. Other than lung microbiomes, oral and airway microbiomes are highly related to lung microbiomes and are therefore included as well. In addition, several lung cancer-associated bacterial genera have been detected by different independent studies. These bacterial genera may not be perfect biomarkers, but they still serve as promising risk factors for lung cancers and show great prognostic value.

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies.

In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.

Establishment and Evaluation of a Porcine Vein Graft Disease Model.

Venous graft disease (VGD) is the leading cause of coronary artery bypass graft (CABG) failure. Large animal models of CABG-VGD are needed for the investigation of disease mechanisms and the development of therapeutic strategies. To perform the surgery, we enter the cardiac chamber through the third intercostal space and carefully dissect the internal mammary vein and immerse it in normal saline. The right main coronary artery is then treated for ischemia. The target vessel is incised, a shunt plug is placed, and the distal end of the graft vein is anastomosed. The ascending aorta is partially blocked, and the proximal end of the graft vein is anastomosed after perforation. The graft vein is checked for patency, and the proximal right coronary artery is ligated. CABG surgery is performed in minipigs to harvest the left internal mammary vein for its use as a vascular graft. Serum biochemical tests are used to evaluate the physiological status of the animals after surgery. Ultrasound examination shows that the proximal, middle, and distal end of the graft vessel are unobstructed. In the surgical model, turbulent blood flow in the graft is observed upon histological examination after the CABG surgery, and venous graft stenosis associated with intimal hyperplasia is observed in the graft. The study here provides detailed surgical procedures for the establishment of a repeatable CABG-induced VGD model.

An ester derivative of tenacigenin B from Marsdenia tenacissima (Roxb.) Wight et Arn reversed paclitaxel-induced MDR in vitro and in vivo by inhibiting both P-gp and MRP2.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima is a medicinal plant, used as a raw material for cancer treatment in China. In our previous studies, 11α-O-2-methylbutanoyl-12ß-O-tigloyl-tenacigenin B (MT2), the main steroid aglycone isolated from M. tenacissima, was found to significantly enhance the antitumor activity of paclitaxel (PTX) in vivo. However, it is unclear whether MT2 reverses multidrug resistance (MDR) in tumors. AIM OF THE STUDY: To determine the role and mechanism of MT2 in reversing tumor MDR. MATERIALS AND METHODS: MDR cell line HeLa/Tax was established from the human cervical carcinoma cell line HeLa by long-term exposure to subtoxic concentrations of PTX and was used to evaluate the ability of MT2 to restore chemosensitivity of cells both in vitro and in a nude mouse model. The expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) was determined using western blotting and immunohistochemistry. The substrate transport function was assessed using an MDR function assay kit. The binding modes of MT2 and P-gp were determined using the conformation-sensitive anti-P-gp antibodies. The permeability and transport properties of MT2 were analyzed in Caco-2 cell monolayers. RESULTS: Compared to parental cells, HeLa/Tax cells overexpress P-gp and MRP2 and are approximately 100-360 fold more resistant to the anticancer drugs PTX, docetaxel, and vinblastine. MT2 at 5 or 10 µmol/L significantly increased the sensitivity of HeLa/Tax to these three anticancer drugs (18-56-fold decrease in IC50 value) and suppressed the expression of P-gp and MRP2. Knockdown of P-gp with small interfering RNA partially reversed MT2-induced sensitivity to PTX in HeLa/Tax cells. Moreover, MT2 directly inhibited P-gp-mediated substrate transport while interacting with membrane P-gp in non-substrate ways. MT2 was highly permeable and could not be transported in the Caco-2 cell monolayers. In nude mice bearing HeLa/Tax xenografts, the combination treatment with MT2 and PTX exerted a synergistic inhibitory effect on the growth of tumors and the expression of P-gp and MRP2 without increasing toxicity. CONCLUSION: MT2 is a potential agent for reversing MDR. It impedes membrane drug efflux pumps by suppressing P-gp and MRP2 expression, and directly inhibiting the transport function of P-gp.

Gas Monitoring in Human Frontal Sinuses-Stability Considerations and Gas Exchange Studies.

Acute rhinosinusitis is a common infectious disease, which, in more than 90% of cases, is caused by viruses rather than by bacteria. Even so, antibiotics are often unnecessarily prescribed, and in the long run this contributes to the alarming level of antibiotics resistance. The reason is that there are no good guiding tools for defining the background reason of the infection. One main factor for the clearance of the infection is if there is non-obstructed ventilation from the sinus to the nasal cavity. Gas in Scattering Media Absorption Spectroscopy (GASMAS) has potential for diagnosing this. We have performed a study of frontal sinuses of volunteers with a focus on signal stability and reproducibility over time, accurate oxygen concentration determination, and assessment of gas transport through passages, naturally and after decongestant spray administration. Different from earlier studies on frontal sinuses, water vapor, serving the purpose of oxygen signal normalization, was measured at 818 nm rather than earlier at 937 nm, now closer to the 760 nm oxygen absorption band and thus resulting in more reliable results. In addition, the action of decongestants was objectively demonstrated for the first time. Evaluated oxygen concentration values for left- and right-hand side sinus cavities were found to agree within 0.3%, and a left-right geometrical asymmetry parameter related to anatomical differences was stable within 10%.

Tribulus terrestris fruit extract inhibits autophagic flux to diminish cell proliferation and metastatic characteristics of oral cancer cells.

Elevated autophagy is highly associated with cancer development and progression. Fruit extracts of several plants inhibit activity of autophagy-related protease ATG4B and autophagy activity in colorectal cancer cells. However, the effects of these plant extracts in oral cancer cells remain unclear. In this study, we found that the extracted Tribulus terrestris fruit (TT-(fr)) and Xanthium strumarium fruit had inhibitory effects on autophagy inhibition in both SAS and TW2.6 oral cancer cells. Moreover, the fruit extracts had differential effects on cell proliferation of oral cancer cells. In addition, the fruit extracts hampered cell migration and invasion of oral cancer cells, particularly in TT-(fr) extracts. Our results indicated that TT-(fr) extracts consistently inhibited autophagic flux, cell growth and metastatic characteristics of oral cancer cells, suggesting TT-(fr) might contain function ingredient to suppress oral cancer cells.

Long-read transcriptome sequencing reveals abundant promoter diversity in distinct molecular subtypes of gastric cancer.

BACKGROUND: Deregulated gene expression is a hallmark of cancer; however, most studies to date have analyzed short-read RNA sequencing data with inherent limitations. Here, we combine PacBio long-read isoform sequencing (Iso-Seq) and Illumina paired-end short-read RNA sequencing to comprehensively survey the transcriptome of gastric cancer (GC), a leading cause of global cancer mortality. RESULTS: We performed full-length transcriptome analysis across 10 GC cell lines covering four major GC molecular subtypes (chromosomal unstable, Epstein-Barr positive, genome stable and microsatellite unstable). We identify 60,239 non-redundant full-length transcripts, of which > 66% are novel compared to current transcriptome databases. Novel isoforms are more likely to be cell line and subtype specific, expressed at lower levels with larger number of exons, with longer isoform/coding sequence lengths. Most novel isoforms utilize an alternate first exon, and compared to other alternative splicing categories, are expressed at higher levels and exhibit higher variability. Collectively, we observe alternate promoter usage in 25% of detected genes, with the majority (84.2%) of known/novel promoter pairs exhibiting potential changes in their coding sequences. Mapping these alternate promoters to TCGA GC samples, we identify several cancer-associated isoforms, including novel variants of oncogenes. Tumor-specific transcript isoforms tend to alter protein coding sequences to a larger extent than other isoforms. Analysis of outcome data suggests that novel isoforms may impart additional prognostic information. CONCLUSIONS: Our results provide a rich resource of full-length transcriptome data for deeper studies of GC and other gastrointestinal malignancies.

Formononetin ameliorates muscle atrophy by regulating myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function in chronic kidney disease.

Muscle atrophy is a common complication in chronic kidney disease (CKD). Inflammation and myostatin play important roles in CKD muscle atrophy. Formononetin (FMN), which is a major bioactive isoflavone compound in Astragalus membranaceus, exerts anti-inflammatory effects and the promotion of myogenic differentiation. Our study is based on myostatin to explore the effects and mechanisms of FMN in relation to CKD muscle atrophy. In this study, CKD rats and tumour necrosis factor α (TNF-α)-induced C2C12 myotubes were used for in vivo and in vitro models of muscle atrophy. The results showed that FMN significantly improved the renal function, nutritional status and inflammatory markers in CKD rats. Values for bodyweight, weight of tibialis anterior and gastrocnemius muscles, and cross-sectional area (CSA) of skeletal muscles were significantly larger in the FMN treatment rats. Furthermore, FMN significantly suppressed the expressions of MuRF-1, MAFbx and myostatin in the muscles of CKD rats and the TNF-α-induced C2C12 myotubes. Importantly, FMN significantly increased the phosphorylation of PI3K, Akt, and FoxO3a and the expressions of the myogenic proliferation and differentiation markers, myogenic differentiation factor D (MyoD) and myogenin in muscles of CKD rats and the C2C12 myotubes. Similar results were observed in TNF-α-induced C2C12 myotubes transfected with myostatin-small interfering RNA (si-myostatin). Notably, myostatin overexpression plasmid (myostatin OE) abolished the effect of FMN on the phosphorylation of the PI3K/Akt/FoxO3a pathway and the expressions of MyoD and myogenin. Our findings suggest that FMN ameliorates muscle atrophy related to myostatin-mediated PI3K/Akt/FoxO3a pathway and satellite cell function.

Automatic Production and Preliminary PET Imaging of a New Imaging Agent [18F]AlF-FAPT.

BACKGROUND: Fibroblast activating protein (FAP) has become an important target for cancer diagnostic imaging and targeted radiotherapy. In particular, [18F]FAPI-42 has been successfully applied to positron emission tomography (PET) imaging of various tumors. However, it exhibits high hepatobiliary metabolism and is thus not conducive to abdominal tumor imaging. This study reports a novel 18F-labeled FAP inhibitor, [18F]AlF-FAPT, a better FAPI imaging agent than [18F]FAPI-42. MATERIALS AND METHODS: The precursor of [18F]AlF-FAPT (NOTA-FAPT) was designed and synthesized using the standard FMOC solid phase synthesis method. [18F]AlF-FAPT was subsequently synthesized and radiolabeled with 18F using the AllInOne synthesis module. Dynamic MicroPET and biodistribution studies of [18F]AlF-FAPT were then conducted in xenograft tumor mouse models to determine its suitability. RESULTS: The precursors NOTA-FAPT were obtained with a chemical purity of > 95%. [18F]AlF-FAPT was synthesized automatically using the cassette-based module AllInOne within 40 min. The non-decay corrected radiochemical yield was 25.0 ± 5.3% (n=3). In vivo imaging and biodistribution studies further demonstrated that compared with [18F]-FAPI-42, [18F]AlF-FAPT had a lower hepatobiliary uptake than [18F]FAPI-42, which was advantageous for imaging abdominal tumors. CONCLUSION: [18F]AlF-FAPT can be synthesized automatically using a one-step method of aluminum fluoride. Collectively, [18F]AlF-FAPT is a better FAPI imaging agent than [18F]FAPI-42. This study proves the feasibility of using [18F]AlF-FAPT as a new radioactive tracer for PET imaging.

Combined one-stage minimally invasive surgery for primary pulmonary carcinoma and mitral regurgitation.

BACKGROUND: We report the first successful short-term outcome of one-stage minimally invasive surgery (MIS) mitral valve repair and video-assisted thoracoscopic surgery (VATS) lobectomy. CASE PRESENTATION: We report the first successful short-term outcome of combined one-stage video-assisted thoracoscopic surgery lobectomy and minimally invasive surgery in a patient with operable primary right upper lobe adenocarcinoma and mitral regurgitation. Post- operative recovery was uneventful, and follow-up at 6 weeks confirmed an excellent surgical and oncologic outcome. CONCLUSIONS: We think one-stage minimally invasive surgery (MIS) cardiac surgery and video-assisted thoracoscopic surgery (VATS) lobectomy would benefit patients with satisfactory cardiac and pulmonary function.