Improving Three-Photon Fluorescence of Near-Infrared Quantum Dots for Deep Brain Imaging by Suppressing Biexciton Decay.

Three-photon fluorescence microscopy (3PFM) is a promising brain research tool with submicrometer spatial resolution and high imaging depth. However, only limited materials have been developed for 3PFM owing to the rigorous requirement of the three-photon fluorescence (3PF) process. Herein, under the guidance of a band gap engineering strategy, CdTe/CdSe/ZnS quantum dots (QDs) emitting in the near-infrared window are designed for constructing 3PF probes. The formation of type II structure significantly increased the three-photon absorption cross section of QDs and caused the delocalization of electron-hole wave functions. The time-resolved transient absorption spectroscopy confirmed that the decay of biexcitons was significantly suppressed due to the appropriate band gap alignment, which further enhanced the 3PF efficiency of QDs. By utilizing QD-based 3PF probes, high-resolution 3PFM imaging of cerebral vasculature was realized excited by a 1600 nm femtosecond laser, indicating the possibility of deep brain imaging with these 3PF probes.

Biosynthesis of CuTe Nanorods with Large Molar Extinction Coefficients for NIR-II Photoacoustic Imaging.

Photoacoustic imaging (PAI) in the second near-infrared region (NIR-II), due to deeper tissue penetration and a lower background interference, has attracted widespread concern. However, the development of NIR-II nanoprobes with a large molar extinction coefficient and a high photothermal conversion efficiency (PCE) for PAI and photothermal therapy (PTT) is still a big challenge. In this work, the NIR-II CuTe nanorods (NRs) with large molar extinction coefficients ((1.31 ± 0.01) × 108 cm-1·M-1 at 808 nm, (7.00 ± 0.38) × 107 cm-1·M-1 at 1064 nm) and high PCEs (70% at 808 nm, 48% at 1064 nm) were synthesized by living Staphylococcus aureus (S. aureus) cells as biosynthesis factories. Due to the strong light-absorbing and high photothermal conversion ability, the in vitro PA signals of CuTe NRs were about 6 times that of indocyanine green (ICG) in both NIR-I and NIR-II. In addition, CuTe NRs could effectively inhibit tumor growth through PTT. This work provides a new strategy for developing NIR-II probes with large molar extinction coefficients and high PCEs for NIR-II PAI and PTT.

Biosynthesis of NIR-II Ag2Se Quantum Dots with Bacterial Catalase for Photoacoustic Imaging and Alleviating-Hypoxia Photothermal Therapy.

Developing the second near-infrared (NIR-II) photoacoustic (PA) agent is of great interest in bioimaging. Ag2Se quantum dots (QDs) are one kind of potential probe for applications in NIR-II photoacoustic imaging (PAI). However, the surfaces with excess anions of Ag2Se QDs, which increase the probability of nonradiative transitions of excitons benefiting PA imaging, are not conducive to binding electron donor ligands for potential biolabeling and imaging. In this study, Staphylococcus aureus (S. aureus) cells are driven for the biosynthesis of Ag2Se QDs with catalase (CAT). Biosynthesized Ag2Se (bio-Ag2Se-CAT) QDs are produced in Se-enriched environment of S. aureus and have a high Se-rich surface. The photothermal conversion efficiency of bio-Ag2Se-CAT QDs at 808 and 1064 nm is calculated as 75.3% and 51.7%, respectively. Additionally, the PA signal responsiveness of bio-Ag2Se-CAT QDs is ≈10 times that of the commercial PA contrast agent indocyanine green. In particular, the bacterial CAT is naturally attached to bio-Ag2Se-CAT QDs surface, which can effectively relieve tumor hypoxia. The bio-Ag2Se-CAT QDs can relieve heat-initiated oxidative stress while undergoing effective photothermal therapy (PTT). Such biosynthesis method of NIR-II bio-Ag2Se-CAT QDs opens a new avenue for developing multifunctional nanomaterials, showing great promise for PAI, hypoxia alleviation, and PTT.

RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma.

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.

Encapsulating Semiconductor Quantum Dots in Supramolecular Cages Enables Ultrafast Guest-Host Electron and Vibrational Energy Transfer.

In the field of supramolecular chemistry, host-guest systems have been extensively explored to encapsulate a wide range of substrates, owing to emerging functionalities in nanoconfined space that cannot be achieved in dilute solutions. However, host-guest chemistry is still limited to encapsulation of small guests. Herein, we construct a water-soluble metallo-supramolecular hexagonal prism with a large hydrophobic cavity by anchoring multiple polyethylene glycol chains onto the building blocks. Then, assembled prisms are able to encapsulate quantum dots (QDs) with diameters of less than 5.0 nm. Furthermore, we find that the supramolecular cage around each QD strongly modifies the photophysics of the QD by universally increasing the rates of QD relaxation processes via ultrafast electron and vibrational energy transfer. Taken together, these efforts expand the scope of substrates in host-guest systems and provide a new approach to tune the optical properties of QDs.

Band Gap Engineering Improves Three-Photon Luminescence of Quantum Dots for Deep Brain Imaging.

Three-photon fluorescence microscopy (3PFM) has emerged as a promising tool in monitoring the structures and functions of the brain. Compared to the various imaging technologies, 3PFM enables a deep-penetrating depth attributed to tighter excitation confinement and suppressed photon scattering. However, the shortage of three-photon probes with a large absorption cross section (σ3) substantially limits its uses. Herein, CdSe/CdS/ZnS quantum dots (QDs) with enhanced 3PF performance were synthesized via the band gap engineering strategy. The introduction of a CdS interlayer with optimized thickness between the emitting CdSe core and the ZnS shell significantly enhanced the 3P absorption cross section of QDs, which originated from the intrinsic piezoelectric polarization effect and the change of the core/shell structure from type-I to quasi-type-II. In addition, the outer ZnS layer compensated the poor electronic passivation of CdS, providing a high level of passivation for the improvement of quantum yield as well as the 3P action cross section of QDs. Under the excitation of a 1600 nm femtosecond laser, PEGylated CdSe/CdS/ZnS QDs were used for in vivo 3PFM imaging of cerebral vessels with high resolution. A tiny capillary with a diameter of 0.8 µm could be resolved at the imaging depth of 1550 µm in a mouse brain with an opened skull. A penetration depth of 850 µm beneath the skull was also achieved using a mouse model with an intact skull.

Activatable Lanthanide Nanoprobes with Dye-Sensitized Second Near-Infrared Luminescence for in Vivo Inflammation Imaging.

Lanthanide nanoparticles exhibit unique photophysical properties and thus emerge as promising second near-infrared (NIR-II) optical agents. However, the limited luminescence brightness hampers their construction of activatable NIR-II probes. Herein, we report the synthesis of dye-sensitized lanthanide nanoprobes (NaGdF4:Nd/ICG; indocyanine green (ICG)) and their further development for in vivo activatable imaging of hypochlorite (ClO-). Dye sensitization using ICG not only shifts the optimal doping concentration of Nd3+ from 5 to 20 mol % but also leads to a 5-fold NIR-II enhancement relative to the ICG-free counterpart. Mechanistic studies reveal that such a luminescence enhancement of NaGdF4:Nd at high Nd3+ concentration is ascribed to an alleviated cross-relaxation effect due to the broad absorption of ICG and faster energy transfer process. Taking advantage of dye oxidation, the nanoprobes enable activatable NIR-II imaging of hypochlorous acid (ClO-) in a drug-induced lymphatic inflammation mouse model. This work thus provides a simple, yet effective luminescence enhancement strategy for constructing lanthanide nanoprobes at higher activator doping concentration toward activatable NIR-II molecular imaging.

Specific gastrointestinal microbiota profiles in Chinese Tan sheep are associated with lauric acid content in muscle.

The biological mechanisms underlying meat quality remain unclear. Currently, many studies report that the gastrointestinal microbiota is essential for animal growth and performance. However, it is uncertain which bacterial species are specifically associated with the meat quality traits. In this study, 16S rDNA and metagenomic sequencing were performed to explore the composition and function of microbes in various gastrointestinal segments of Tan sheep and Dorper sheep, as well as the relationship between microbiota and meat quality (specifically, the fatty acid content of the muscle). In the ruminal, duodenal, and colonic microbiome, several bacteria were uniquely identified in respective breeds, including Agrobacterium tumefaciens, Bacteroidales bacterium CF, and several members of the family Oscillospiraceae. The annotation of GO, KEGG, and CAZYme revealed that these different bacterial species were linked to the metabolism of glucose, lipids, and amino acids. Additionally, our findings suggested that 16 microbial species may be essential to the content of fatty acids in the muscle, especially C12:0 (lauric acid). 4 bacterial species, including Achromobacter xylosoxidans, Mageeibacillus indolicus, and Mycobacterium dioxanotrophicus, were positively correlated with C12:0, while 13 bacteria, including Methanobrevibacter millerae, Bacteroidales bacterium CF, and Bacteroides coprosuis were negatively correlated with C12:0. In a word, this study provides a basic data for better understanding the interaction between ruminant gastrointestinal microorganisms and the meat quality traits of hosts.

Equivalent cut-off values of Bath Ankylosing Spondylitis Disease Activity Index corresponding to Ankylosing Spondylitis Disease Activity Score cut-off values.

OBJECTIVES: To define the equivalent cut-off values of Bath ankylosing Spondylitis Disease Activity Index (BASDAI) for discriminating disease activity corresponding to Ankylosing Spondylitis Disease Activity Score (ASDAS) cut-off values, and to determine the equivalent change units for determining the clinically improvement between ΔBASDAI and ΔASDAS-CRP. METHODS: 475 patients with axial spondyloarthritis (axSpA) whose data on BASDAI and ASDAS were available were included. Among them, 154 (32.4%) patients whose data on ΔBASDAI and ΔASDAS-CRP were available. Receiver-operator curve (ROC) with area under curve (AUC) was used to determine the BASDAI cut-off values that best corresponded to ASDAS-CRP. The Cohen's kappa was utilised to assess the degree of agreement between disease activity states based on BASDAI and ASDAS cut-off values, and clinically improvement between ΔBASDAI and ΔASDAS-CRP. RESULTS: According to the ASDAS-CRP, 88 (18.6%), 130 (27.4%), 191 (40.1%) and 66 (13.9%) patients were classified as inactive, moderate, high and very high disease activities, respectively. ROC revealed that BASDAI values 1.6 (AUC: 0.948), 2.9 (AUC: 0.790) and 3.8 (AUC: 0.875) best corresponded to ASDAS-CRP values 1.3, 2.1 and 3.5, respectively. The degree of agreement between them was moderate (kappa: 0.527). The ΔBASDAI 1.6 (AUC: 0.745) and 2.0 (AUC: 0.708) best corresponded to the ΔASDAS-CRP 1.1 (minimal clinically important improvement) and 2.0 (major improvement), respectively. The degree of agreement was good (kappa: 0.685). CONCLUSIONS: The BASDAI values 1.6, 2.9 and 3.8 correspond to ASDAS-CRP values 1.3, 2.1 and 3.5, respectively. The ΔBASDAI 1.6 and 2.0 best correspond to the ΔASDAS-CRP 1.1 and 2.0, respectively.

Calcium ionophore improves embryonic development and pregnancy outcomes in patients with previous developmental problems in ICSI cycles.

BACKGROUND: Calcium (Ca2+) ionophores are now mainly considered as efficient treatments for fertilization failure. Recently, its application for rescuing poor embryo development was proposed but still non-routine. This study aimed to explore whether Ca2+ ionophore improves embryo development and pregnancy outcomes in patients with poor embryo development in previous intracytoplasmic sperm injection (ICSI) cycles. METHODS: This study included 97 patients undergoing assisted oocyte activation (AOA) with Ca2+ ionophore (calcimycin, A23187) treatment. Preimplantation embryonic development and clinical outcomes were compared between ICSI-AOA cycles (AOA group) and previous ICSI cycles of the same patients in which poor embryo developmental potential was present (non-AOA group). Subgroups stratified by maternal age (< 35, 35-40, ≥ 40 years, respectively) were analyzed separately. RESULTS: A total of 642 MII oocytes were collected in AOA group, and 689 in non-AOA group. Significantly higher day 3 good quality embryo rate (P = 0.034), good quality blastocyst formation rate (P <  0.001), and utilization rate (P <  0.001) were seen in AOA group. Similar results were seen in each subgroup. For pregnancy outcomes, there were significant differences in clinical pregnancy rate (P = 0.039) and live birth rate (P = 0.045) in total group. In subgroup aged < 35 years, biochemical (P = 0.038), clinical (P = 0.041), and ongoing pregnancy rate (P = 0.037) in AOA group were significantly higher than that in non-AOA group. No significant improvement for clinical outcomes for subgroups aged 35-40 and aged ≥40. CONCLUSION: The study suggests that calcimycin could improve preimplantation development and pregnancy outcomes in patients aged < 35 years with embryo developmental problems in previous ICSI cycles.

Primary ewing sarcoma in the uterine cervix with multiple bone metastases.

A 45-year-old female (G1, P1) with HPV-52 infection and low-grade cervical cytology presented to our clinic with an asymptomatic cervical mass. She suffered amenorrhea for the past 3 years due to medication for thyroid cancer. Magnetic resonance imaging revealed a mass sized 7.1 × 6.3 × 5.7 cm in the cervix with local invasion, and multiple lesions in the left ilium and femur. Histologically blue small round cells, positive for CD99 and FLI-1, obtained by cervical biopsy and the EWSR1 gene rearrangement detected by Fluorescence in situ hybridization confirmed the diagnosis of Ewing sarcoma. However, prior to the first cycle of systemic chemotherapy, the patient developed a sudden onset of lower extremities paraplegia, with PET/CT detecting extensive metastatic lesions in multiple bones including cervical 4 and thoracic 10 vertebral bodies. Although we performed emergency spinal canal decompression and excision of a thoracic 10 metastasis, the patient's condition deteriorated rapidly and died three months later.

Calcification of lower extremity arteries is related to the presence of osteoporosis in postmenopausal women with type 2 diabetes mellitus: a cross-sectional observational study.

It is unknown whether there is any relationship between extremity arterial macroangiopathy and osteoporosis in type 2 diabetic mellitus (T2DM) patients. We provide evidence to show the association between lower extremity arterial calcification and the presence of osteoporosis in postmenopausal T2DM women, but not in T2DM men of similar age. PURPOSE: To investigate the relationship between lower extremity arterial calcification and the presence of osteoporosis in type 2 diabetic mellitus (T2DM) patients. METHODS: We performed a retrospective cross-sectional study in patients with T2DM. They were assigned into two groups (patients with or without vascular calcification) in both sexes. Clinical characteristics, presence of osteoporosis, and bone metabolic markers were compared. Arterial calcification was determined by ultrasonography examination. Osteoporosis was defined based on the measurements from dual-energy X-ray absorptiometry. The relationship between the lower extremity arterial calcification and the presence of osteoporosis was analyzed. Statistical analysis was performed in SPSS 26.0. RESULTS: A total of 933 T2DM patients (535 men ≥ 50 years old, and 398 postmenopausal women) were identified and analyzed. A significant association between arterial calcification and osteoporosis was only observed in women, with a higher prevalence of osteoporosis observed in women with calcification (40.8%) than in women without calcification (26.9%) (P = 0.004). Compared to women without calcification, women with calcification had lower bone mineral densities in the hip (P < 0.001) and femoral neck (P < 0.001). Ordinal logistic regression analysis showed that women with calcification had a nearly 2-fold increased risk for osteoporosis, even after adjusting for age, duration of T2DM, body mass index, pulse pressure, clearance of creatinine, glycosylated hemoglobin, and fasting C-peptide. Similar differences were not identified between men with and without calcification. CONCLUSION: Calcification of lower extremity arteries is related with the presence of osteoporosis in postmenopausal T2DM women.

Bright quantum dots emitting at ∼1,600 nm in the NIR-IIb window for deep tissue fluorescence imaging.

With suppressed photon scattering and diminished autofluorescence, in vivo fluorescence imaging in the 1,500- to 1,700-nm range of the near-IR (NIR) spectrum (NIR-IIb window) can afford high clarity and deep tissue penetration. However, there has been a lack of NIR-IIb fluorescent probes with sufficient brightness and aqueous stability. Here, we present a bright fluorescent probe emitting at ∼1,600 nm based on core/shell lead sulfide/cadmium sulfide (CdS) quantum dots (CSQDs) synthesized in organic phase. The CdS shell plays a critical role of protecting the lead sulfide (PbS) core from oxidation and retaining its bright fluorescence through the process of amphiphilic polymer coating and transferring to water needed for imparting aqueous stability and compatibility. The resulting CSQDs with a branched PEG outer layer exhibited a long blood circulation half-life of 7 hours and enabled through-skin, real-time imaging of blood flows in mouse vasculatures at an unprecedented 60 frames per second (fps) speed by detecting ∼1,600-nm fluorescence under 808-nm excitation. It also allowed through-skin in vivo confocal 3D imaging of tumor vasculatures in mice with an imaging depth of ∼1.2 mm. The PEG-CSQDs accumulated in tumor effectively through the enhanced permeation and retention effect, affording a high tumor-to-normal tissue ratio up to ∼32 owing to the bright ∼1,600-nm emission and nearly zero autofluorescence background resulting from a large ∼800-nm Stoke's shift. The aqueous-compatible CSQDs are excreted through the biliary pathway without causing obvious toxicity effects, suggesting a useful class of ∼1,600-nm emitting probes for biomedical research.

Role of leptin in the regulation of food intake in fasted mice.

Leptin is well acknowledged as an anorexigenic hormone that plays an important role in feeding control. Hypothalamic GABA system plays a significant role in leptin regulation on feeding and metabolism control. However, the pharmacological relationship of leptin and GABA receptor is still obscure. Therefore, we investigated the effect of leptin or combined with baclofen on the food intake in fasted mice. We detected the changes in hypothalamic c-Fos expression, hypothalamic TH, POMC and GAD67 expression, plasma insulin, POMC and GABA levels to demonstrate the mechanisms. We found that leptin inhibit fasting-induced increased food intake and activated hypothalamic neurons. The inhibitory effect on food intake induced by leptin in fasted mice can be reversed by pretreatment with baclofen. Baclofen reversed leptin's inhibition on c-Fos expression of PAMM in fasted mice. Therefore, these results indicate that leptin might inhibit fasting-triggered activation of PVN neurons via presynaptic GABA synaptic functions which might be partially blocked by pharmacological activating GABA-B. Our findings identify the role of leptin in the regulation of food intake.

The Role of Lysophosphatidic Acid Receptors in Ovarian Cancer: A Minireview.

Lysophosphatidic acid (LPA) is a bioactive lipid component of ovarian cancer activating factor, which is present at a high concentration in the ascitic fluid and plasma of patients with ovarian cancer. A group of six lysophosphatidic acid receptors (LPARs), LPAR1 through LPAR6, which belong to the G protein-coupled receptor superfamily (GPCR), mediate cellular activities of LPA and activates a series of downstream molecules and cellular responses, including biological and pathological effects. LPARs are widely expressed in normal ovary, benign tumor, and ovarian cancer tissues and cancer cell lines with a broad range of levels. The LPA/LPAR axis is involved in tumorigenesis and development of ovarian cancer through mediating the cellular responses to LPA and influencing the expression and function of oncogenic molecules. In the present review, the roles of LPARs in ovarian cancer, including the expression, function, and downstream molecules, are summarized, and we discuss the implications for ovarian cancer treatment that targets LPARs.

Noninvasive In Vivo Imaging in the Second Near-Infrared Window by Inorganic Nanoparticle-Based Fluorescent Probes.

The fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) has emerged as a new method for in vivo imaging and attracted considerable attention in the past decade. Owing to the suppressed photon scattering and diminished autofluorescence, in vivo fluorescence imaging in NIR-II window can afford deep tissue penetration depth with high clarity. Inorganic nanoparticle-based fluorescent probes in the NIR-II window have greatly prospered the field into a development stage because of their superior traits, including adjustable emission covering the whole NIR-II window and abundant surface functional groups that facilitate chemical modification and bioconjugation, etc. In this Feature, we introduce the unique imaging performance of the NIR-II optical window and highlight the latest development of noninvasive biological fluorescent imaging in NIR-II window using inorganic nanoparticle-based probes. A perspective on the challenge and future direction of inorganic nanoparticle-based NIR-II probes is also discussed.

Role of 5-HT receptors in neuropathic pain: potential therapeutic implications.

5-HT plays a crucial role in the progress and adjustment of pain both centrally and peripherally. The therapeutic action of the 5-HT receptors` agonist and antagonist in neuropathic pain have been widely reported in many studies. However, the specific roles of 5-HT subtype receptors have not been reviewed comprehensively. Therefore, we summarized the recent findings on multiple subtypes of 5-HT receptors in both central and peripheral nervous system in neuropathic pain, particularly, 5-HT1, 5-HT2, 5-HT3 and 5-HT7 receptors. In addition, 5-HT4, 5-HT5 and 5-HT6 receptors were also reviewed. Most of studies focused on the function of 5-HT subtype receptors in spinal level compared to brain areas. Based on these evidences, the pain process can be facilitated or inhibited that depending on the specific subtypes and the distribution of 5-HT receptors. Therefore, this review may provide potential therapeutic implications in treatment of neuropathic pain.

METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer.

BACKGROUND: As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. METHODS: qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. RESULTS: Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the "reader" protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. CONCLUSIONS: Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

LPAR1 regulates the development of intratumoral heterogeneity in ovarian serous cystadenocarcinoma by activating the PI3K/AKT signaling pathway.

BACKGROUND: To explore the role of lysophosphatidic acid receptor 1 (LPAR1) and its correlation with the PI3K/AKT pathway in the development of intratumoral heterogeneity (ITH) in human ovarian serous cystadenocarcinoma (OSC). METHODS: Immunohistochemical staining was performed to detect LPAR1 expression in matched primary and recurrent lesions from the same patients. Cell models of ITH were established using the limiting dilution methodology and Transwell invasion/migration assays. LPAR1 expression in the ITH cell models was silenced or upregulated with lentiviral particles, and the biological characteristics were evaluated using various in vitro and in vivo assessments of cell function. The levels of phosphorylated PI3K/AKT (p-PI3K/p-AKT) in LPAR1 knockdown and LPAR1-overexpressing cells were detected. RESULTS: The H-scores for LPAR1 staining in the lymphatic metastatic and recurrent lesions were noticeably higher than in the primary tumor lesions from the same patients (P = 0.024/0.031). High LPAR1 expression was associated with worse progression-free survival and overall survival (P = 0.017/0.039). Biological functions in vitro, including invasion, migration, and proliferation, and tumor formation in vivo were decreased in the LPAR1-silenced cells (all P < 0.05). These cellular functions were significantly increased in the LPAR1-overexpressing cells in vitro and in vivo (all P < 0.05). The levels of p-PI3K and p-AKT were significantly decreased in the LPAR1 knockdown cells and significantly increased in the LPAR1-overexpressing cells (all P < 0.05). CONCLUSIONS: Higher levels of the LPAR1 protein were associated with a poor prognosis. LPAR1 plays essential roles in the invasion, migration, and proliferation of heterogeneous subsets of OSC cell lines and the development of ITH of OSC, possibly by modulating the activity of the PI3K/AKT signaling pathway.