Combined treatment of All-trans retinoic acid with Tamoxifen suppresses ovarian cancer.

BACKGROUND: Ovarian cancer is a malignant tumor of the female reproductive system, and its mortality rate is as high as 70%. Estrogen receptor α (ERα)-positive ovarian cancer accounted for most of all ovarian cancer patients. ERα can promote the growth and proliferation of tumors. METHODS: The combined effect of All-trans retinoic acid (ATRA) and tamoxifen was obtained by the combination screening of tamoxifen and compound library by MTS. In addition, colony formation assay, flow cytometry analysis, immunofluorescence staining, quantitative real-time polymerase chain reaction (PCR), western blot, and tumor xenotransplantation models were used to further evaluate the efficacy of tamoxifen and ATRA in vitro and in vivo for ER-α-positive ovarian cancer. RESULTS: In our study, we found that All-trans retinoic acid (ATRA) can cooperate with tamoxifen to cause cell cycle arrest and apoptosis and inhibit ERα-positive ovarian cancer in vivo and in vitro. Further exploration of the mechanism found that ATRA can Inhibit genes related to the ERα signaling pathway, enhance the sensitivity of ERα-positive ovarian cancer cells to tamoxifen, and ascertain the effectiveness of tamoxifen and ATRA as treatments for ovarian cancer with an ERα-positive status. CONCLUSION: Combination of ATRA and tamoxifen is a new way for the treatment of ERα-positive ovarian cancer.

Endoscopic Endonasal Internal Carotid Artery Transposition Technique in Tumor With Parasellar Extension: A Single-Center Experience.

BACKGROUND AND OBJECTIVES: Lateralization or mobilization of the internal carotid artery (ICA) during a midline approach is required to expose lesions behind or lateral to the ICA. However, there have been no published data regarding the surgical outcomes of the endoscopic endonasal internal carotid transposition technique (EEITT). This study aimed to analyze the relevant surgical anatomy around the ICA and propose a grading scheme of EEITT. METHODS: A retrospective review of patients who underwent EEITT at a single institution was performed. Based on structures that limited the ICA and intraoperative findings, an anatomically surgical grading scheme of EEITT was proposed. RESULTS: Forty-two patients (mean age 45.6 years, 57.1% female patients) were included. Of them, 29 cases (69.0%) were Knosp grade 4 pituitary adenoma, 6 cases (14.3%) were chordoma, 6 cases (14.3%) were meningioma, and a single case (2.4%) was meningeal IgG4-related disease. The EEITT was categorized into Grades 1, 2 and 3, which was used in 24 (57.1%), 12 (28.6%), and 6 (14.3%) cases, respectively. The most common symptom was visual disturbance (45.2%). The gross total resection rate in Grade 1 (79.2%) and Grade 2 (83.3%) was much higher than that in Grade 3 (66.6%). The overall rate of visual function improvement, preoperative cranial nerve (CN) palsy improvement, and postoperative hormonal remission was 89.4%, 85.7%, and 88.9%, respectively. The rate for the following morbidities was cerebrospinal fluid leakage, 2.4%; permanent diabetes insipidus, 4.8%; new transient CN palsy, 9.5%; permanent CN palsy, 4.7%; panhypopituitarism, 7.1%; and ICA injury, 2.4%. CONCLUSION: The EEITT is technically feasible and could be graded according to the extent of disconnection of limiting structures. For complex tumor with parasellar extensions, the distinction into Grades 1, 2, and 3 will be of benefit to clinicians in predicting risks, avoiding complications, and generating tailored individualized surgical strategies.

Extended Endoscopic Endonasal Approach for Giant Pediatric Craniopharyngiomas: Technical Note and Case Series.

BACKGROUND AND OBJECTIVES: Giant pediatric craniopharyngiomas are rare tumors whose clinical and surgical management is extremely challenging. A variety of open transcranial approaches has been used to resect these lesions. Although there has been an increasing acceptance of the endoscopic endonasal approach (EEA) for the resection of pediatric craniopharyngiomas in recent years, many surgeons continue to recommend against the use of the EEA for giant pediatric craniopharyngiomas. This study aimed to evaluate the feasibility of extended EEA for giant craniopharyngiomas in the pediatric population. METHODS: All consecutive pediatric patients with giant craniopharyngiomas (diameter >4 cm) who underwent endoscopic endonasal surgery at our institution were retrospectively reviewed. Data on demographic information, preoperative assessment, imaging features, surgical results, complications, and recurrences were recorded and analyzed. RESULTS: A total of 16 pediatric patients with an average age of 12 years were identified. The mean maximum diameter and volume of the tumors were 4.35 cm and 24.1 cm3, respectively. Gross total resection was achieved in 13 patients (81.3%) and subtotal resection in 3 patients (18.7%). Postoperatively, partial or complete anterior pituitary insufficiency occurred in 100% of patients, and 62.5% developed new-onset diabetes insipidus. Visual function improved in 9 patients (56.3%) and remained stable in 7 patients (43.7%). Postoperative cerebrospinal fluid leakage occurred in 2 patients and was successfully repaired through the EEA. During a mean follow-up of 44.3 months, 18.8% of patients had a >9% increase in body mass index, and 93.8% of patients successfully returned to school or work. Two patients (12.5%) suffered a recurrence. Disease control was achieved in 16 patients (100%) at final follow-up. CONCLUSION: The extended EEA allows adequate access to this challenging tumor and enables complete resection and visual improvement with a reasonable approach-related complication rate.

Cu-Tremella fuciformis polysaccharide-based tumor microenvironment-responsive injectable gels for cuproptosis-based synergistic osteosarcoma therapy.

Cuproptosis affects osteosarcoma locally, and the exploitation of cuproptosis-related biomaterials for osteosarcoma treatment is still in its infancy. We designed and synthesized a novel injectable gel of Cu ion-coordinated Tremella fuciformis polysaccharide (TFP-Cu) for antiosteosarcoma therapy. This material has antitumor effects, the ability to stimulate immunity and promote bone formation, and a controlled Cu2+ release profile in smart response to tumor microenvironment stimulation. TFP-Cu can selectively inhibit the proliferation of K7M2 tumor cells by arresting the cell cycle and promoting cell apoptosis and cuproptosis. TFP-Cu also promoted the M1 polarization of RAW264.7 cells and regulated the immune microenvironment. These effects increased osteogenic gene and protein expression in MC3T3-E1 cells. TFP-Cu could significantly limit tumor growth in tumor-bearing mice by inducing tumor cell apoptosis and improving the activation of anti-CD8 T cell-mediated immune responses. Therefore, TFP-Cu could be a potential candidate for treating osteosarcoma and bioactive drug carrier for further cancer-related applications.

Mechanism of acacetin regulating hepatic stellate cell apoptosis based on network pharmacology and experimental verification.

Background: Hepatic fibrosis is caused by various liver diseases and eventually develops into liver cancer. There is no specific drug approved for the treatment of hepatic fibrosis in the world. Acacetin (AC), a natural flavonoid, is widely present in nature in various plants, such as black locust, Damiana, Silver birch. It has been reported that acacetin can inhibit the proliferation of cancer cells and induce apoptosis. Purpose: In this study, we investigated the effect of acacetin on hepatic stellate cell apoptosis, thereby improving hepatic fibrosis, and combined experimental validation and molecular docking to reveal the underlying mechanism. Result: First, we discovered that acacetin inhibited hepatic stellate cell proliferation as well as the expression of fibrosis-related proteins α-smooth muscle actin (α-SMA) and collagen type I 1 gene (COL1A1) in LX2 cells. Acacetin was then found to promote apoptosis of hepatic stellate cells through the caspase cascade pathway. Network pharmacology screening showed that TP53, CASP3, CASP8, BCL2, PARP1, and BAX were the most important targets related to apoptosis in the PPI network. GO and KEGG analyses of these six important targets were performed, and the top 10 enriched biological processes and related signaling pathways were revealed. Further network pharmacology analysis proved that apoptosis was involved in the biological process of acacetin's action against hepatic stellate cells. Finally, molecular docking revealed that acacetin binds to the active sites of six apoptotic targets. In vitro experiments further confirmed that acacetin could promote the apoptosis of LX2 cells by inducing the activation of P53, thereby improving hepatic fibrosis. Conclusion: acacetin induces P53 activation and promotes apoptosis of hepatic stellate cells thereby ameliorating hepatic fibrosis.

Melanin-mediated accumulation of polycyclic aromatic hydrocarbons in human hair: Insights from biomonitoring and cell exposure studies.

While human hair is widely used to monitor micro-organic contaminants (MOCs), their incorporation mechanisms are poorly understood. Melanin, known to facilitate the accumulation of drugs in hair, hasn't been studied in the field of MOCs. Here, polycyclic aromatic hydrocarbons (PAHs), a class of priority MOCs, were investigated through hair biomonitoring as well as cell exposure experiments. PAH concentrations and melanin contents were measured in black and white hairs from the same individual. The results showed that five dominant PAHs (phenanthrene, fluoranthene, pyrene, benzo[a]anthracene and chrysene) in black hair (0.66 ng/g - 35.1 ng/g) were significantly higher than those in white hair (0.52 ng/g - 29.6 ng/g). Melanin contents in black hair (14.9 - 48.9 ng/g) were markedly higher than in white hair (0.35 - 2.15 ng/g) and were correlated to PAH concentrations, hinting melanin-mediated accumulation of PAHs in hair. The in vitro experiment using murine melanoma cells demonstrates that PAH levels in cells were affected by melanin, suggesting the affinity of melanin to PAHs. Both biomonitoring and cell exposure experiment implicate the pivotal role of melanin in PAH accumulation in hair. Therefore, to ensure the accuracy of hair biomonitoring for MOCs, attention must be paid to the melanin content uniformity.

Mesonephric-like adenocarcinoma of the ovary.

Mesonephric-like adenocarcinoma is a new class of rare subtypes of the female reproductive system. Its clinical symptoms are similar to other types of ovarian tumors. The diagnosis is based on pathological and immunohistochemical methods. The main treatment option is surgery combined with chemotherapy. Few cases have been reported at home and abroad. We reported a case of a 45-year-old woman with a cystic solid mass in the left adnexa. The postoperative pathological diagnosis was mesonephric-like adenocarcinoma of the left ovary and mature cystic teratoma (partial infiltration of the small intestine). This case had no specific clinical symptoms. Immunohistochemical findings showed positive results of GATA3, TTF1, CD10, ER, and PR. Paclitaxel and carboplatin chemotherapy were given after the operation. Currently, no specific criteria are available for diagnosis and treatment of the disease. This article aims to improve the understanding of clinicians in this disease and create a basis for clinical diagnosis and treatment.

Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma.

Background: Recent research has shown that lysosomes play a critical role in the onset and progression of malignancy by regulating tumor cell death through several mechanisms. Nevertheless, the involvement of lysosome-associated genes (LSAGs) in lung adenocarcinoma (LUAD) is still not well understood. Methods: LSAGs were identified in malignant lung epithelial cells, as well as biologically and functionally annotated by the comprehensive integration of single-cell and bulk RNA-sequencing data. Prognostic characterization of LSAGs was established, of which the accuracy and reliability were assessed by one-way Cox and LASSO regression. Correlations between LSAG properties and immune cell infiltration, chemotherapy, and immunotherapy were analyzed by integrated omics data. Finally, we characterized the expression of three LSAGs (KCNE1, NPC2, and SFTPD) in malignant lung epithelium and assessed their impact on tumor malignancy related phenotypes. Results: We identified 18 LSAGs associated with prognosis, of which 3 LSAGs were used to construct prognostic models. High-risk patients had worse survival and the model predicted it better than other clinical indicators. Based on the functional enrichment analyses, LSAGs were associated with binding and molecular activity functions, inhibition of DNA damage repair and tumor growth, IL7 signaling pathway, and glycolysis. M0 macrophages and M1 macrophages were substantially enriched in high-risk patients. Conversely, there was a considerable enrichment of resting dendritic cells and M2 macrophages in patients at low risk. We also found that risk scores predicted the outcome of immunotherapy. In vitro, we found that KCNE1, NPC2, and SFTPD were lowly expressed in malignant epithelial cells and patients with low expression of KCNE1, NPC2, and SFTPD had a higher percentage of M2 macrophage infiltration. Overexpression of KCNE1, NPC2, and SFTPD suppressed the proliferation and invasion of malignant cells, and M0 macrophages remarkably reduced M2 macrophage polarization and cellular secretion of pro-tumor cytokines. Conclusions: We used three LASGs-KCNE1, NPC2, and SFTPD-to develop and validate a predictive signature for LUAD patients. Furthermore, we found that low expression of KCNE1, NPC2, and SFTPD promotes lung cancer cell proliferation and invasion and M2 macrophage polarization. Our study may provide fresh perspectives for customized immunotherapy.

Study on the vertical Bridgman method of melt-grown CsPbBr3 single crystals for nuclear radiation detection.

As an excellent representative of all-inorganic perovskite materials, CsPbBr3 has been widely used in high-energy rays or high-energy particles detection for its outstanding high carrier mobility and long diffusion length. The great challenges and opportunities in these fields are crystal growth technology, especially the high-quality and large-sized CsPbBr3 single crystals. In this work, the influences of growth parameters (temperature gradient, growth rate, cooling rate) and thermal stress by the vertical Bridgman method on the quality and performance of CsPbBr3 crystals are systematically studied. The final results show that 10°C cm-1 is the optimized temperature gradient and 0.5 mm h-1 is the suitable growth rate for CsPbBr3 crystal growth. The study also shows that a cooling rate of 10°C h-1 for the general temperature interval and 1°C h-1 for the phase transition temperature interval is helpful to balance crystal growth efficiency as well as crystal quality. Crystal cracks caused by thermal stress as well as crystal adhesion on the ampoule can be effectively solved by depositing a uniform carbon film on the ampoule in advance. The optical, electrical and detection performance are also investigated. The optical characterization in the wavelength region ranging from ultraviolet to infrared indicates the crystal has a low density of deep-level defects and good crystal quality. The resistivity over 109 Ω cm and µτ of electrons over 10-2 cm-2 V-1 proves that the electrical performance of the crystal has met the basic requirement for nuclear radiation detection. The metal-semiconductor-metal structure Ti/Ni/CsPbBr3/Ni/Ti detector fabricated from the optimized CsPbBr3 single crystal has an energy resolution of 12.85% (137Cs, 662 keV). The purpose of this work is to provide a useful guide and reference for the future exploration of repeatable and improvable CsPbBr3 crystal growth technology.

Further investigation of the lateral approach for the resection of Knosp grade 4 pituitary adenomas in endoscopic endonasal surgery.

OBJECTIVE: The authors performed a further in-depth study of the lateral compartment of the cavernous sinus (LCCS) by the endoscopic endonasal approach to improve the safety and efficacy of the lateral approach for the removal of Knosp grade 4 pituitary adenomas (KG4PAs). METHODS: Twenty-three cadaveric specimens were used for endoscopic endonasal dissection, and the LCCS was exposed to observe the neurovascular and fibrous structures within. A subclassification of the lateral approach based on further knowledge of the LCCS was proposed and used to resect 86 KG4PAs, and the surgical outcomes of these cases were reviewed. Type A KG4PAs represent tumor that was mainly distributed in the posterosuperior and superolateral compartments, type B KG4PAs represent tumor that was mainly distributed in the anteroinferior compartments, and type AB KG4PAs represent tumor that extended into each compartment with characteristics of types 4A and 4B. RESULTS: The authors identified multiple fibers that anchored the horizontal segment of the internal carotid artery (ICA) to the abducens nerve. The fibers, the sympathetic nerve, and the inferior lateral trunk form a partition-like structure in the LCCS named the abducens nerve-ICA complex (AIC), and the LCCS can be divided into the superolateral and inferolateral compartments by the AIC. Accordingly, the lateral approach was subclassified into the lateral superior (LS) approach and the anterior inferior (AI) approach. The LS approach was mainly used to resect type A KG4PAs, whereas the AI approach was used to resect type B KG4PAs, and a combination of the two was used to resect type AB KG4PAs. The gross-total, subtotal, and partial resection rates were 81.4%, 12.8%, and 5.8%, respectively. The numbers of cases of postoperative transient cranial nerve palsy, postoperative permanent cranial nerve palsy, ICA injury, and CSF leakage were 6 (6.9%), 2 (2.3%), 1 (1.2%), and 1 (1.2%), respectively. CONCLUSIONS: This study revealed that the LCCS is divided by the AIC into the superolateral and inferolateral compartments, avoiding the misconception that the LCCS has vertical communication. Therefore, the lateral approach was subclassified into the LS approach and the AI approach for the resection of KG4PAs, which allowed a high gross-total resection rate with acceptable safety in the surgical treatment of KG4PAs.

Exploring the interplay between methylation patterns and non-coding RNAs in non-small cell lung cancer: Implications for pathogenesis and therapeutic targets.

Lung cancer is a global public health issue, with non-small cell lung cancer (NSCLC) accounting for 80-85 % of cases. With over two million new diagnoses annually, understanding the complex evolution of this disease is crucial. The development of lung cancer involves a complex interplay of genetic, epigenetic, and environmental factors, leading the key oncogenes and tumor suppressor genes to disorder, and activating the cancer related signaling pathway. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNA (circRNAs) are unique RNA transcripts with diverse biological functions. These ncRNAs are generated through genome transcription and play essential roles in cellular processes. Epigenetic modifications such as DNA methylation, N6-methyladenosine (m6A) modification, and histone methylation have gained significant attention in NSCLC research. The complexity of the interactions among these methylation modifications and ncRNAs contribute to the precise regulation of NSCLC development. This review comprehensively summarizes the associations between ncRNAs and different methylation modifications and discusses their effects on NSCLC. By elucidating these relationships, we aim to advance our understanding of NSCLC pathogenesis and identify potential therapeutic targets for this devastating disease.

Potential dosimetric error in the adaptive workflow of a 1.5 T MR-Linac from patient movement relative to immobilisation systems.

In magnetic resonance- (MR-) based adaptive workflows for an MR-linac, the treatment plan is optimized and recalculated online using the daily MR images. The Unity MR-linac is supplied with a patient positioning device (ppd) using pelvic and abdomen thermoplastic masks attached to a board with high-density components. This study highlights the dosimetric effect of using this in such workflows when there are relative patient-ppd displacements, as these are not visualized on MR imaging and the treatment planning system assumes the patient is fixed relative to the ppd. The online adapted plans of two example rectum cancer patients treated at a Unity MR-linac were perturbed by introducing relative patient-ppd displacements, and the effect was evaluated on plan dosimetry. Forty-eight perturbed clinical adapted plans were recalculated, based on online MR-based synthetic computed tomography, and compared with the original plans, using dose-volume histogram parameters and gamma analysis. The target volume covered by the prescribed dose ( D pre ) and by at least 107% of D pre varied up to - 1.87% and + 3.67%, respectively for 0.5 cm displacements, and to - 3.18% and + 4.96% for 2 cm displacements; whilst 2%-2 mm gamma analysis showed a median value of 92.9%. The use of a patient positioning system with high-density components in a Unity MR-based online adaptive treatment workflow can introduce unrecognized errors in plan dosimetry and it is recommended not to use such a device for such treatments, without modifying the device and the workflow, followed by careful clinical evaluation, or alternatively to use other immobilization methods.

Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer.

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.

Applications of Near-Infrared Fluorescence Imaging and Angiography of Inferior Vesical Artery in Laparoscopic Lateral Lymph Node Dissection: A Prospective Nonrandomized Controlled Study.

BACKGROUND: Near-infrared imaging with indocyanine green has been used to guide lateral lymph node dissection, yet its efficacy and benefits need further investigation. OBJECTIVE: To investigate the efficacy and feasibility of near-infrared fluorescence imaging and angiography of the inferior vesical artery in laparoscopic lateral lymph node dissection. DESIGN: A prospective nonrandomized controlled study. SETTINGS: Single-center study. PATIENTS: Patients with lower rectal cancer who underwent total mesorectal excision plus lateral lymph node dissection. MAIN OUTCOME MEASURES: A cohort of 108 patients was enrolled. After propensity score matching, 29 patients in the near-infrared group and 50 patients in the non-near-infrared group were matched. The total number of harvested lateral lymph nodes, positive lateral lymph nodes, inferior vesical artery preservation, and postoperative urinary function were compared. RESULTS: After propensity score matching, both groups had similar baseline characteristics. The total number of harvested lateral lymph nodes in the near-infrared group was significantly higher (12 vs 9, p = 0.013), but positive lateral lymph nodes were similar between the 2 groups (1 vs 1, p = 0.439). The inferior vesical artery preservation ratio was significantly increased with the aid of indocyanine green angiography (93.1% vs 56.0%, p < 0.001). The non-near-infrared group required more days for urinary catheter removal than the near-infrared group (5 vs 4, p = 0.046). Urinary recatheterization tended to occur more frequently in the non-near-infrared group, with a marginally significant trend (16% vs 0%, p = 0.059). The non-near-infrared group tended to have more cases with residual urine volume ≥50 mL than the near-infrared group (20.0% vs 3.4%, p = 0.087), especially in the bilateral dissection subgroup (41.2% vs 0%, p = 0.041). LIMITATIONS: Small sample size. CONCLUSIONS: Near-infrared imaging increased the number of harvested lateral lymph nodes, whereas real-time indocyanine green fluorescence angiography ensured the preservation of the inferior vesical artery and tended to improve postoperative urinary function.

Transcriptome-based approach to identify mechanisms underlying locomotor abnormality induced by decabromodiphenyl ethane in zebrafish larvae.

The brominated flame retardant decabromodiphenyl ethane (DBDPE) has been extensively used following restrictions on BDE-209 and thus, been frequently detected in aquatic environment. However, information on impact of DBDPE on fish development and the potential mechanisms remains scarce. In present study, developing zebrafish were employed as a study model. Embryos were exposed until 5 d to DBDPE at concentrations of 0, 3, 30, and 300 µg/L, following which the impact on larval development was investigated. DBDPE bioaccumulation and locomotor hyperactivity were observed in developing zebrafish exposed to DBDPE. Transcriptome and bioinformatics analyses indicated that pathways associated with cardiac muscle contraction and retinol metabolism were notably affected. The mechanisms of DBDPE to induce locomotor abnormality were further investigated by analyzing levels of retinol and retinol metabolites, eye and heart histology, heart rates, and ATPase activity. Our results indicate that locomotor hyperactivity observed in larvae exposed to DBDPE results from abnormal heartbeat, which in turn is attributable to inhibition of Na+/K+-ATPase activity. Furthermore, DBDPE did not change larval eye histology and contents of retinoid (retinol, retinal, and retinoic acid). This study provides insight into the mechanisms underlying DBDPE-induced developmental toxicity and highlights the need for addressing the environmental risks for aquatic organisms.

Dopamine, Norepinephrine and Serotonin Participate Differently in Methylphenidate Action in Concomitant Behavioral and Ventral Tegmental Area, Locus Coeruleus and Dorsal Raphe Neuronal Study in Young Rats.

Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1-6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects.

Feasibility of delta radiomics-based pCR prediction for rectal cancer patients treated with magnetic resonance-guided adaptive radiotherapy.

Magnetic resonance-guided adaptive radiotherapy (MRgART) represents the latest frontier in precision radiotherapy. It is distinguished from other modalities by the possibility of acquiring high-contrast soft tissue images, combined with the ability to recalculate and re-optimize the plan on the daily anatomy. The extensive database of available images offers ample scope for using disciplines such as radiomics to try to correlate features and outcomes. This study aimed to correlate the change of radiomics feature along the treatment to pathological complete response (pCR) for locally advanced rectal cancer (LARC) patients. Twenty-eight LARC patients undergoing neoadjuvant chemoradiotherapy (nCRT) with a short course (25 Gy, 5 Gy × 5f) MRgART at 1.5 Tesla MR-Linac were enrolled. The T2-weighted images acquired at each fraction, corresponding target delineation, pCR result of the surgical specimen, and clinical variables were collected. Seven families of features [First Order, Shape, Gray-level Co-occurrence Matrix (GLCM), Gray-level Dependence Matrix (GLDM), Gray-level Run Length Matrix (GLRLM), Gray-level Size Zone Matrix (GLSZM), and Neighborhood Gray Tone Difference Matrix (NGTDM)] were extracted, and delta features were calculated from the ratio of features of each successive fraction to those of the first fraction. Mann-Whitney U test and LASSO were utilized to reduce the dimension of features and select those features that are most significant to pCR. At last, the radiomics signatures were established by linear regression with the final set of features and their coefficients. A total of 581 radiomics features were extracted, and 2,324 delta features were calculated for each patient. Nineteen features and delta features, and one clinical variable (cN) were significant (p< 0.05) to pCR; seven predictive features were further selected and included in the linear regression to construct the radiomics signature significantly discriminating pCR and non-pCR groups (p< 0.05). Delta features based on MRI images acquired during a short course MRgART could potentially be used to predict treatment response in LARC patients undergoing nCRT.

Radiogenomic landscape: Assessment of specific phagocytosis regulators in lower-grade gliomas.

Genome-wide CRISPR-Cas9 knockout screens have emerged as a powerful method for identifying key genes driving tumor growth. The aim of this study was to explore the phagocytosis regulators (PRs) specifically associated with lower-grade glioma (LGG) using the CRISPR-Cas9 screening database. Identifying these core PRs could lead to novel therapeutic targets and pave the way for a non-invasive radiogenomics approach to assess LGG patients' prognosis and treatment response. We selected 24 PRs that were overexpressed and lethal in LGG for analysis. The identified PR subtypes (PRsClusters, geneClusters, and PRs-score models) effectively predicted clinical outcomes in LGG patients. Immune response markers, such as CTLA4, were found to be significantly associated with PR-score. Nine radiogenomics models using various machine learning classifiers were constructed to uncover survival risk. The area under the curve (AUC) values for these models in the test and training datasets were 0.686 and 0.868, respectively. The CRISPR-Cas9 screen identified novel prognostic radiogenomics biomarkers that correlated well with the expression status of specific PR-related genes in LGG patients. These biomarkers successfully stratified patient survival outcomes and treatment response using The Cancer Genome Atlas (TCGA) database. This study has important implications for the development of precise clinical treatment strategies and holds promise for more accurate therapeutic approaches for LGG patients in the future.

Label-free microfluidic chip for segregation and recovery of circulating leukemia cells: clinical applications in acute myeloid leukemia.

We present a label-free microfluidic chip for the segregation of circulating leukemia cells (CLCs) from blood samples, with a focus on its clinical applications in Acute Myeloid Leukemia (AML). The microfluidic chip achieved an approximate capture efficiency of 92%. The study analyzed a comprehensive set of 66 blood specimens from AML patients in different disease stages, including newly diagnosed and relapsing cases, patients in complete remission, and those in partial remission. The results showed a significant difference in CLC counts between active disease stages and remission stages (p < 0.0001), with a proposed threshold of 5 CLCs to differentiate between the two. The microfluidic chip exhibited a sensitivity of 95.4% and specificity of 100% in predicting disease recurrence. Additionally, the captured CLCs were subjected to downstream molecular analysis using droplet digital PCR, allowing for the identification of genetic mutations associated with AML. Comparative analysis with bone marrow aspirate processing by FACS demonstrated the reliability and accuracy of the microfluidic chip in tracking disease burden, with highly agreement results obtained between the two methods. The non-invasive nature of the microfluidic chip and its ability to provide real-time insights into disease progression make it a promising tool for the proactive monitoring and personalized patient care of AML.

Phenotypic and Proteomic Insights into Differential Cadmium Accumulation in Maize Kernels.

The contamination of agricultural soil with cadmium (Cd), a heavy metal, poses a significant environmental challenge, affecting crop growth, development, and human health. Previous studies have established the pivotal role of the ZmHMA3 gene, a P-type ATPase heavy metal transporter, in determining variable Cd accumulation in maize grains among 513 inbred lines. To decipher the molecular mechanism underlying mutation-induced phenotypic differences mediated by ZmHMA3, we conducted a quantitative tandem mass tag (TMT)-based proteomic analysis of immature maize kernels. This analysis aimed to identify differentially expressed proteins (DEPs) in wild-type B73 and ZmHMA3 null mutant under Cd stress. The findings demonstrated that ZmHMA3 accumulated higher levels of Cd compared to B73 when exposed to varying Cd concentrations in the soil. In comparison to soil with a low Cd concentration, B73 and ZmHMA3 exhibited 75 and 142 DEPs, respectively, with 24 common DEPs shared between them. ZmHMA3 showed a higher induction of upregulated genes related to Cd stress than B73. Amino sugar and nucleotide sugar metabolism was specifically enriched in B73, while phenylpropanoid biosynthesis, nitrogen metabolism, and glyoxylate and dicarboxylate metabolism appeared to play a more significant role in ZmHMA3. This study provides proteomics insights into unraveling the molecular mechanism underlying the differences in Cd accumulation in maize kernels.