Engineering miniature CRISPR-Cas Un1Cas12f1 for efficient base editing.

Adeno-associated virus (AAV) is a relatively safe and efficient vector for gene therapy. However, due to its 4.7-kb limit of cargo, SpCas9-mediated base editors cannot be packaged into a single AAV vector, which hinders their clinical application. The development of efficient miniature base editors becomes an urgent need. Un1Cas12f1 is a class II V-F-type CRISPR-Cas protein with only 529 amino acids. Although Un1Cas12f1 has been engineered to be a base editor in mammalian cells, the base-editing efficiency is less than 10%, which limits its therapeutic applications. Here, we developed hypercompact and high-efficiency base editors by engineering Un1Cas12f1, fusing non-specific DNA binding protein Sso7d, and truncating single guide RNA (sgRNA), termed STUminiBEs. We demonstrated robust A-to-G conversion (54% on average) by STUminiABEs or C-to-T conversion (45% on average) by STUminiCBEs. We packaged STUminiCBEs into AAVs and successfully introduced a premature stop codon on the PCSK9 gene in mammalian cells. In sum, STUminiBEs are efficient miniature base editors and could readily be packaged into AAVs for biological research or biomedical applications.

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear. PATIENTS AND METHODS: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC. RESULTS: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis. CONCLUSION: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

Hypothalamic vasopressin sex differentiation is observed by embryonic day 15 in mice and is disrupted by the xenoestrogen bisphenol A.

Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVPPVN) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth ( embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVPPVN neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVPPVN neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP+ by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVPPVN neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVPPVN neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVPPVN sex differentiation, which is impacted by prenatal BPA exposure.

Diagnostic Value of Transabdominal Ultrasonography in Gastrointestinal Malignant Tumors.

Objective: To explore the application value of transabdominal ultrasonography in the diagnosis of gastrointestinal malignant tumors. Methods: This study retrospectively analyzed the transabdominal ultrasound imaging data of 284 patients with gastrointestinal tumors admitted to our hospital from April 2019 to March 2022 and assessed the accuracy of transabdominal ultrasound in diagnosing different types of gastrointestinal tumor diseases. The diagnostic accuracy of transabdominal ultrasonography for TNM staging of gastrointestinal malignancies was calculated. Results: The sensitivity and specificity of transabdominal ultrasonography in the diagnosis of gastric cancer were (82.40% and 83.72%, respectively), colon cancer (77.78% and 88.35%, respectively), gastric stromal tumor (95.45% and 93.65%, respectively), gastric lymphoma (72.22% and 94.66%, respectively), colorectal lymphoma (80.00% and 95.42%, respectively), gastric mucosal hypertrophy (85.71% and 96.69%, respectively), and pyloric hypertrophy (92.59% and 97.79%, respectively). Among the 284 patients included, 152 patients had malignant tumors, including 34 patients with stage I, 30 patients with stage II, 51 patients with stage III, and 37 patients with stage IV. The accuracy of transabdominal ultrasonography for TNM staging of gastrointestinal malignancies was 85.53% (130/152). Conclusion: Transabdominal ultrasonography shows promise as a diagnostic tool for gastrointestinal malignant tumors; however, it is recommended to be used in conjunction with other detection methods such as fibrous gastrointestinal tract examination to minimize the risk of missed diagnoses and misdiagnoses. The study highlights the potential of transabdominal ultrasonography as a non-invasive and accessible diagnostic method for gastrointestinal malignancies. Further research and advancements in imaging technologies are crucial for enhancing diagnostic capabilities and improving patient outcomes in the future.

Optimizing breast cancer diagnosis with photoacoustic imaging: An analysis of intratumoral and peritumoral radiomics.

Background: The differentiation between benign and malignant breast tumors extends beyond morphological structures to encompass functional alterations within the nodules. The combination of photoacoustic (PA) imaging and radiomics unveils functional insights and intricate details that are imperceptible to the naked eye. Purpose: This study aims to assess the efficacy of PA imaging in breast cancer radiomics, focusing on the impact of peritumoral region size on radiomic model accuracy. Materials and methods: From January 2022 to November 2023, data were collected from 358 patients with breast nodules, diagnosed via PA/US examination and classified as BI-RADS 3-5. The study used the largest lesion dimension in PA images to define the region of interest, expanded by 2 mm, 5 mm, and 8 mm, for extracting radiomic features. Techniques from statistics and machine learning were applied for feature selection, and logistic regression classifiers were used to build radiomic models. These models integrated both intratumoral and peritumoral data, with logistic regressions identifying key predictive features. Results: The developed nomogram, combining 5 mm peritumoral data with intratumoral and clinical features, showed superior diagnostic performance, achieving an AUC of 0.950 in the training cohort and 0.899 in validation. This model outperformed those based solely on clinical features or other radiomic methods, with the 5 mm peritumoral region proving most effective in identifying malignant nodules. Conclusion: This research demonstrates the significant potential of PA imaging in breast cancer radiomics, especially the advantage of integrating 5 mm peritumoral with intratumoral features. This approach not only surpasses models based on clinical data but also underscores the importance of comprehensive radiomic analysis in accurately characterizing breast nodules.

Exosome, a Rising Biomarkers in Liquid Biopsy: Advances of Label-Free and Label Strategy for Diagnosis of Cancer.

Cancer is commonly considered as one of the most severe diseases, posing a significant threat to human health and society due to various serious challenges. These challenges include difficulties in accurate diagnosis and a high propensity to form metastasis. Tissue biopsy remains the gold standard for diagnosing and subtyping cancer. However, concerns arise from its invasive nature and the potential risk of metastasis during these complex diagnostic procedures. Meanwhile, liquid biopsy has recently witnessed the rapid advancements with the emergence of three prominent detection biomarkers: circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes. Whereas, the very low abundance of CTCs combined with the instability of ctDNA intensify the challenges and decrease the accuracy of these two biomarkers for cancer diagnosis. While exosomes have gained widespread recognition as a promising biomarker in liquid biopsy due to their relatively low-invasive detection method, excellent biostability, rich resources, high abundance, and ability to provide valuable information about cancer. Therefore, it is crucial to systematically summarize recent advancements mainly in exosome-based detection methods for early cancer diagnosis. Specifically, this review will primarily focus on label-based and label-free strategies for detecting cancer using exosomes. We anticipate that this comprehensive analysis will enhance readers' understanding of the significance and value of exosomes in the fields of cancer diagnosis and therapy.

Olaparib and niraparib as maintenance therapy in patients with newly diagnosed and platinum-sensitive recurrent ovarian cancer: A single-center study in China.

BACKGROUND: Poly adenosine-diphosphate-ribose polymerase (PARP) inhibitors (PARPi) have been approved to act as first-line maintenance (FL-M) therapy and as platinum-sensitive recurrent maintenance (PSR-M) therapy for ovarian cancer in China for >5 years. Herein, we have analyzed the clinical-application characteristics of olaparib and niraparib in ovarian cancer-maintenance therapy in a real-world setting to strengthen our understanding and promote their rational usage. METHODS: A retrospective chart review identified patients with newly diagnosed or platinum-sensitive recurrent ovarian cancer, who received olaparib or niraparib as maintenance therapy at Sichuan Cancer Hospital between August 1, 2018, and December 31, 2021. Patient medical records were reviewed. We grouped and analyzed patients based on the type of PARPi they used (the olaparib group and the niraparib group) and the line of PARPi maintenance therapy (the FL-M setting and the PSR-M setting). The primary endpoint was the 24-month progression-free survival (PFS) rate. RESULTS: In total, 131 patients (olaparib: n = 67, 51.1%; niraparib: n = 64, 48.9%) were enrolled. Breast cancer susceptibility genes (BRCA) mutations (BRCAm) were significantly less common in the niraparib group than in the olaparib group [9.4% (6/64) vs. 62.7% (42/67), P <0.001], especially in the FL-M setting [10.4% (5/48) vs. 91.4% (32/35), P <0.001]. The 24-month PFS rates in the FL-M and PSR-M settings were 60.4% and 45.7%, respectively. In patients with BRCAm, the 24-month PFS rates in the FL-M and PSR-M settings were 62.2% and 72.7%, respectively. CONCLUSIONS: Olaparib and niraparib were effective in patients with ovarian cancer without any new safety signals except for skin pigmentation. In patients with BRCAm, the 24-month PFS of the PARPi used in the PSR-M setting was even higher than that used in the FL-M setting.

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.

Multimorbidity and mortality among older patients with coronary heart disease in Shenzhen, China.

BACKGROUND: The current understanding of the magnitude and consequences of multimorbidity in Chinese older adults with coronary heart disease (CHD) is insufficient. We aimed to assess the association and population-attributable fractions (PAFs) between multimorbidity and mortality among hospitalized older patients who were diagnosed with CHD in Shenzhen, China. METHODS: We conducted a retrospective cohort study of older Chinese patients (aged ≥ 65 years) who were diagnosed with CHD. Cox proportional hazards models were used to estimate the associations between multimorbidity and all-cause and cardiovascular disease (CVD) mortality. We also calculated the PAFs. RESULTS: The study comprised 76,455 older hospitalized patients who were diagnosed with CHD between January 1, 2016, and August 31, 2022. Among them, 70,217 (91.9%) had multimorbidity, defined as the presence of at least one of the predefined 14 chronic conditions. Those with cancer, hemorrhagic stroke and chronic liver disease had the worst overall death risk, with adjusted HRs (95% CIs) of 4.05 (3.77, 4.38), 2.22 (1.94, 2.53), and 1.85 (1.63, 2.11), respectively. For CVD mortality, the highest risk was observed for hemorrhagic stroke, ischemic stroke, and chronic kidney disease; the corresponding adjusted HRs (95% CIs) were 3.24 (2.77, 3.79), 1.91 (1.79, 2.04), and 1.81 (1.64, 1.99), respectively. All-cause mortality was mostly attributable to cancer, heart failure and ischemic stroke, with PAFs of 11.8, 10.2, and 9.1, respectively. As for CVD mortality, the leading PAFs were heart failure, ischemic stroke and diabetes; the corresponding PAFs were 18.0, 15.7, and 6.1, respectively. CONCLUSIONS: Multimorbidity was common and had a significant impact on mortality among older patients with CHD in Shenzhen, China. Cancer, heart failure, ischemic stroke and diabetes are the primary contributors to PAFs. Therefore, prioritizing improved treatment and management of these comorbidities is essential for the survival prognosis of CHD patients from a holistic public health perspective.

Nomogram predictive models for adult patients with acute lymphoblastic leukaemia based on real-world treatment outcomes.

This study aimed to analyse the characteristics and treatment outcomes of adult patients with acute lymphoblastic leukaemia (ALL) and construct nomogram predictive models for prognosis prediction. Between January 2017 and June 2022, 462 adult patients with ALL were included in this retrospective analysis. Patients' ages ranged from 14 to 84 years. B-cell origin was observed in 82.7% of these patients, while 17.3% of the cases were of T-cell origin. The BCR/ABL1 fusion gene was detected in 32.9% of those with B-ALL. Complete remission was achieved in 83.7% of the patients after induction chemotherapy. The median disease-free survival (DFS) and overall survival (OS) of patients were 19.0 and 39.1 months, respectively. The 5-year DFS and OS rates were 29.5% and 41.8%, respectively. The BCR/ABL1 fusion gene had a significant adverse impact on DFS and OS when patients were treated with tyrosine kinase inhibitors (TKIs) and chemotherapy; however, this effect was eliminated when patients underwent transplantation. Multivariate analysis identified that age ≥ 35 years, white blood cell count ≥ 30 × 109/L, platelet count < 100 × 109/L, failure to achieve complete remission after induction chemotherapy, positive measurable residual disease (MRD), and absence of transplantation were independent adverse prognostic factors for DFS and/or OS. Nomogram predictive models constructed by the rms package in R software based on these prognostic factors demonstrated precise predictive value. In conclusion, adult patients with ALL experience poor survival. TKIs in combination with transplantation can eliminate the adverse effects of BCR/ABL1 fusion genes on prognosis. Nomogram predictive models were accurate for prognostic prediction and will be useful in clinical practice.

Robust miniature Cas-based transcriptional modulation by engineering Un1Cas12f1 and tethering Sso7d.

The miniature V-F CRISPR-Cas12f system has been repurposed for gene editing and transcription modulation. The small size of Cas12f satisfies the packaging capacity of adeno-associated virus (AAV) for gene therapy. However, the efficiency of Cas12f-mediated transcriptional activation varies among different target sites. Here, we developed a robust miniature Cas-based transcriptional activation or silencing system using Un1Cas12f1. We engineered Un1Cas12f1 and the cognate guide RNA and generated miniCRa, which led to a 1,319-fold increase in the activation of the ASCL1 gene. The activity can be further increased by tethering DNA-binding protein Sso7d to miniCRa and generating SminiCRa, which reached a 5,628-fold activation of the ASCL1 gene and at least hundreds-fold activation at other genes examined. We adopted these mutations of Un1Cas12f1 for transcriptional repression and generated miniCRi or SminiCRi, which led to the repression of ∼80% on average of eight genes. We generated an all-in-one AAV vector AIOminiCRi used to silence the disease-related gene SERPINA1. AIOminiCRi AAVs led to the 70% repression of the SERPINA1 gene in the Huh-7 cells. In summary, miniCRa, SminiCRa, miniCRi, and SminiCRi are robust miniature transcriptional modulators with high specificity that expand the toolbox for biomedical research and therapeutic applications.

Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.

BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

A cross-sectional study of the association between breastfeeding history and overweight/obesity in postmenopausal women.

OBJECTIVES: This study endeavors to augment comprehension of the association between breastfeeding and maternal weight within Asian populations. METHODS: Data were obtained from the comprehensive 2011 research titled "Risk Evaluation of Cancers in Chinese Diabetic Individuals (REACTION): a longitudinal analysis," focusing specifically on postmenopausal women residing in the metropolitan precincts of Guiyang. It presents a cross-sectional study involving 5,987 parous postmenopausal women, aged 60.1 ± 6.9 years, who underwent assessments of body mass index and waist-to-height ratio. The probability of excessive weight or obesity was evaluated in relation to the aggregate duration of breastfeeding, using single-factor and multivariate logistic regression analyses. RESULTS: Following multiple adjustments for different confounders, the odds ratios (ORs) demonstrated that women who had borne a single child and breastfed for more than 12 months exhibited an increased prevalence of excessive weight (body mass index ≥24 kg/m 2 ) in contrast to those who abstained from breastfeeding (model I: OR, 1.481; 95% confidence interval, 1.124-1.952; P = 0.005; model II: OR, 1.471; 95% confidence interval, 1.113-1.944; P = 0.007). Conversely, among the subset of women who had given birth to two or more children, no noteworthy associations emerged between breastfeeding duration and the propensity for excessive weight or obesity (all models). CONCLUSION: In the Asian population, the duration of breastfeeding does not appear to be necessarily linked to the prevalence of overweight or obesity in postmenopausal women.

Artificial intelligence-assisted system for the assessment of Forrest classification of peptic ulcer bleeding: a multicenter diagnostic study.

BACKGROUND: Inaccurate Forrest classification may significantly affect clinical outcomes, especially in high risk patients. Therefore, this study aimed to develop a real-time deep convolutional neural network (DCNN) system to assess the Forrest classification of peptic ulcer bleeding (PUB). METHODS: A training dataset (3868 endoscopic images) and an internal validation dataset (834 images) were retrospectively collected from the 900th Hospital, Fuzhou, China. In addition, 521 images collected from four other hospitals were used for external validation. Finally, 46 endoscopic videos were prospectively collected to assess the real-time diagnostic performance of the DCNN system, whose diagnostic performance was also prospectively compared with that of three senior and three junior endoscopists. RESULTS: The DCNN system had a satisfactory diagnostic performance in the assessment of Forrest classification, with an accuracy of 91.2% (95%CI 89.5%-92.6%) and a macro-average area under the receiver operating characteristic curve of 0.80 in the validation dataset. Moreover, the DCNN system could judge suspicious regions automatically using Forrest classification in real-time videos, with an accuracy of 92.0% (95%CI 80.8%-97.8%). The DCNN system showed more accurate and stable diagnostic performance than endoscopists in the prospective clinical comparison test. This system helped to slightly improve the diagnostic performance of senior endoscopists and considerably enhance that of junior endoscopists. CONCLUSION: The DCNN system for the assessment of the Forrest classification of PUB showed satisfactory diagnostic performance, which was slightly superior to that of senior endoscopists. It could therefore effectively assist junior endoscopists in making such diagnoses during gastroscopy.

Functional gonadotroph pituitary adenoma: A case report.

Most clinically non-functioning pituitary tumour arise from gonadotroph cells. However, clinically functional pituitary gonadotroph adenoma is rare. Here we report a female case who presented with menstrual disturbances, however further workup demonstrated a pituitary microadenoma with elevated FSH and oestradiol level. Transsphenoidal resection was performed and the surgical histopathology confirmed pituitary gonadotroph adenoma. Postoperatively, improvement in both symptoms and hormonal profile were observed. Interestingly, the initially enlarged and polycystic ovaries became within normal range around eight months after the surgery. We suggest functional gonadotroph adenoma should be considered in the presence of gynaecological disorder with persistently elevated oestradiol and FSH levels.

Acute Administration of Lactate Exerts Antidepressant-like Effect Through cAMP-dependent Protein Synthesis.

Lactate acts as an important metabolic substrate and signalling molecule modulating neural activities in the brain, and recent preclinical and clinical studies have revealed its antidepressant effect after acute or chronic peripheral administration. However, the neural mechanism underlying the antidepressant effect of lactate, in particular when lactate is acutely administered remains largely unknown. In the current study, we focused on forced swimming test (FST) to elucidate the neural mechanisms through which acute intracerebroventricular (ICV) infusion of lactate exerts antidepressant-like effect. A total of 238 male Sprague Dawley rats were used as experimental subjects. Results showed lactate produced antidepressant-like effect, as indicated by reduced immobility, in a dose- and time-dependent manner. Moreover, the antidepressant-like effect of lactate was dependent of new protein synthesis but not new gene expression, lactate's metabolic effect or hydroxy-carboxylic acid receptor 1 (HCAR1) activation. Furthermore, lactate rapidly promoted dephosphorylation of eukaryotic elongation factor 2 (eEF2) and increased brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus in a cyclic adenosine monophosphate (cAMP)-dependent manner. Finally, inhibition of cAMP production blocked the antidepressant-like effect of lactate. These findings suggest that acute administration of lactate exerts antidepressant-like effect through cAMP-dependent protein synthesis.

Myelodysplasia-related gene mutations are associated with favorable prognosis in patients with TP53-mutant acute myeloid leukemia.

This study aimed to examine the characteristics and treatment outcomes of patients with TP53-mutant acute myeloid leukaemia (AML) and to explore potential prognostic factors. This retrospective analysis included 130 patients diagnosed with TP53-mutant AML at the Fujian Medical University Union Hospital between January 2016 and June 2023. Patients' ages ranged from 17 to 80 years, with a median age of 59 years. The proportions of de novo, therapy-related, and secondary AML cases were 71.5%, 7.7%, and 20.8%, respectively. Complex karyotypes were observed in 60.6% of patients, and the proportions of -5 or del(5q), -7 or del(7q), and - 17 or del(17p) were 41.7%, 27.9% and 14.4%, respectively. DNA methylation- and myelodysplasia-related (MR) gene mutations were observed in 36.9% and 25.4% of patients, respectively. These patients showed poor survival, with a median overall survival (OS) of 4.5 months, a 1-year OS rate of 32.5%, a 3-year OS rate of 18.8%, and a 5-year OS rate of 11.3%. The complete response rates for intensive chemotherapy (IC), hypomethylating agent (HMAs)-based therapies, and azacitidine plus venetoclax were 35.7%, 22.2%, and 37.5%, respectively. Patients who did or did not receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) had similar prognoses (median OS: 6.0 vs. 3.9 months; P = 0.6415). Multivariate analysis indicated that MR gene mutations is an independent favorable prognostic factor of OS (HR = 0.366, 95% CI: 0.181-0.738, P = 0.005). In conclusion, patients with TP53-mutant AML have poor prognoses under current treatment strategies and MR gene mutations are associated with a more favorable survival. Therefore, further studies are needed to improve the survival rates in this population.

Effect of lung rehabilitation training combined with nutritional intervention on patients after thoracoscopic resection of lung cancer.

Thoracoscopic lobectomy is the main type of surgical treatment for lung cancer. Postoperative patients have complications and decreased pulmonary function, which affects their discharge time and quality of life. Lung ventilator training has been shown to promote the postoperative recovery of patients; however, no specific treatment plan has been approved to enhance lung rehabilitation. Therefore, it is necessary to explore methods to promote the postoperative rehabilitation of patients with lung cancer. The patients with lung cancer who were admitted to Banan Hospital Affiliated to Chongqing Medical University (Chongqing, China) between January 2022 and January 2023, and who planned to undergo a thoracoscopic lobectomy, were randomly categorized into two groups. The experimental group began lung rehabilitation training 2 weeks before the operation and received individualized nutrition programs. The control group did not receive lung rehabilitation training and nutrition programs. The quality of life, lung function, 6-min walking distance (6MWD), nutritional status, postoperative complications, hospital expenses and hospital stay between the two groups were compared. Finally, 86 and 83 patients were included in the test and control groups, respectively. Regarding the postoperative indicators, the patients in the test group scored higher in all areas of quality of life, exhibited higher lung function and 6MWD, and had significantly higher serum total protein, albumin and hemoglobin levels, and body mass index, compared with the control group. Furthermore, the incidence of postoperative pulmonary complications, the duration of hospitalization and the hospitalization costs were lower in the experimental group. In conclusion, lung rehabilitation training combined with nutritional intervention can promote the postoperative rehabilitation of patients with lung cancer. The research has been duly registered in the Chinese Clinical Trial Register platform (registration no. ChiCTR2300078681; registered Dec 15, 2023).

CD57-positive CD8 + T cells define the response to anti-programmed cell death protein-1 immunotherapy in patients with advanced non-small cell lung cancer.

Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC). However, accurately identifying patients who will benefit from immunotherapy remains a challenge. This study aimed to discover potential biomarkers for predicting immunotherapy response in NSCLC patients. Single-cell mass cytometry (CyTOF) was utilized to analyze immune cell subsets in peripheral blood mononuclear cells (PBMCs) obtained from NSCLC patients before and 12 weeks after single-agent immunotherapy. The CyTOF findings were subsequently validated using flow cytometry and multiplex immunohistochemistry/immunofluorescence in PBMCs and tumor tissues, respectively. RNA sequencing (RNA-seq) was performed to elucidate the underlying mechanisms. In the CyTOF cohort (n = 20), a high frequency of CD57+CD8+ T cells in PBMCs was associated with durable clinical benefit from immunotherapy in NSCLC patients (p = 0.034). This association was further confirmed in an independent cohort using flow cytometry (n = 27; p < 0.001), with a determined cutoff value of 12.85%. The cutoff value was subsequently validated in another independent cohort (AUC = 0.733). We also confirmed the CyTOF findings in pre-treatment formalin-fixed and paraffin-embedded tissues (n = 90; p < 0.001). RNA-seq analysis revealed 475 differentially expressed genes (DEGs) between CD57+CD8+ T cells and CD57-CD8+ T cells, with functional analysis identifying DEGs significantly enriched in immune-related signaling pathways. This study highlights CD57+CD8+ T cells as a promising biomarker for predicting immunotherapy success in NSCLC patients.

Co, Fe Dual-Doped MoS2 Nanosheets on Polypyrrole Microtubes as Effective Peroxidase Mimics for Glutathione Sensing.

Heteroatom doping is considered an effective way to enhance the catalytic activity of MoS2 nanosheets (NSs). In the paper, dual-metal doping was proposed to incorporate Fe and Co into hierarchical MoS2 ultrathin NSs, which grew directly on polypyrrole microtubes (Fe, Co-MoS2@PPy), for the enhanced enzyme-like catalytic reaction. The particular hollow tubular structure realized effective electron transfer. The doped Fe and Co tuned the electronic architecture of the MoS2 NSs to enhance the enzyme-like catalytic activity. The abundant exposed void spaces facilitated ion diffusion/penetration between the PPy interlayer and Fe-Co doped MoS2 shell, leading to heterostructured synergistic effects. Therefore, the synthesized Fe and Co-MoS2@PPy composites showed remarkable catalytic activity. The high catalytic efficiency of Fe and Co-MoS2@PPy was confirmed with the reaction of tetramethylbenzidine (TMB) and H2O2 for visible detection. The blue color disappeared after adding glutathione (GSH). Thus, this procedure was used as a convenient way to detect GSH with a detection limit of 0.76 µM. The dual-metal-doped strategy was confirmed to improve the performance of MoS2 nanocomposites and could be used as a promising matrix for other applications, such as electrochemical energy conversion, medical diagnosis, and others.