Histology and transcriptomic analysis reveal the inflammation and affected pathways under 2-methylisoborneol (2-MIB) exposure on grass carp.

2-Methylisoborneol (2-MIB) is a common and widely distributed off-flavor compound in water. However, the toxic mechanisms of 2-MIB on aquatic organisms remain largely unexplored. In this study, grass carp larvae were exposed to different concentrations (0, 5, and 20 µg L-1) of 2-MIB for 96 h. The accumulation of 2-MIB in the dorsal muscle was measured. Histological analysis, ultrastructure observations, and transcriptomic sequencing were conducted on the liver tissues. The results showed that 2-MIB accumulated significantly in the fish muscle, with the accumulation increasing as the exposure concentration increased through gas chromatography-mass spectrometry (GC-MS) detection. Histological and ultrastructure observations indicated that 2-MIB caused concentration-dependent inflammatory infiltration and mitochondrial damage in the liver. Transcriptomic analysis revealed lipid metabolism disorders induced by exposure to 2-MIB in grass carp. Additionally, 5 µg L-1 2-MIB affected the neurodevelopment and cardiovascular system of grass carp larvae through extracellular matrix (ECM)-receptor interaction and focal adhesion pathway. Furthermore, several pathways related to the digestive system were significantly enriched, implying that 2-MIB may impact pancreatic secretion function, protein digestion and absorption processes. These findings provide new insights into the potential toxicological mechanisms of 2-MIB.

3D porous conductive matrix based on phase-transited BSA and covalent coupling-stabilized transition ZnS-CNT for antifouling and on-site detection of nitrite in soil.

Nitrite plays a critical role in a variety of nitrification and denitrification processes in the nitrogen cycle. Due to the high surface energy, tendency to aggregate, and poor conductivity, current nitrite ZnS-based sensing platform could not meet the need of on-site nitrite detection in smart agriculture. In order to address these issues, the carboxylated carbon nanotube (CNT) was introduced to reduce the surface energy and prevented aggregation of ZnS, while ZnS-carboxylated CNT (ZnS-CNT) composite also provided excellent electrochemical conductivity. Furthermore, the introduction of phase transition BSA (PTB) created a three-dimensional porous conductive matrix without interfering with the mass transfer process of nitrite. The resulting sensing platform exhibited a linear detection range of 10 nM to 0.4 mM for nitrite, with a detection limit of 0.73 nM. And this sensing platform had the excellent antifouling ability to direct detection nitrite in real soil suspension. In addition, the sensing platform demonstrated remarkable resistance to interferences from pH variations, microbial presence, and organic pollutants that usually present in soil environment. Therefore, on-site detection of nitrite ions in soil environment was realized no needing complex pretreatments.

Low-Complexity Tracking Control of Unknown Strict-Feedback Systems With Quantitative Performance Guarantees.

This article is concerned with the prescribed performance tracking control problem for the strict-feedback systems with unknown nonlinearities and unmatched disturbances. The challenge lies in the realization of a complete performance specification for trajectory tracking in the sense of quantitatively regulating the peak value, overshoot, settling time, and accuracy while ensuring that the initial condition holds naturally. To this end, an error transformation, equipped with a shifting function, is introduced and incorporated with a new-type barrier function. Then, a class of performance functions is exploited to quantify the settling times and steady-state bounds of the intermediate errors. Moreover, to improve the flexibility of formulating performance specifications for the tracking error, a pair of asymmetric performance boundaries are further designed. With their combination, a novel robust prescribed performance control (PPC) approach is proposed in this article. It not only achieves the quantitative performance guarantees but also preserves the unique simplicity of PPC, evading the needs for function approximation, parameter identification, disturbance estimation, derivative calculation, or command filtering. The above theoretical findings are confirmed via three simulation studies.

Stability and variability of molecular subtypes: comparative analysis of primary and metastatic triple-negative breast cancer.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive cancer. Although our previous study classified primary TNBC into four subtypes, comprehensive longitudinal investigations are lacking. METHODS: We assembled a large-scale, real-world cohort comprised of 880 TNBC patients [465 early-stage TNBC (eTNBC) and 415 metastatic TNBC (mTNBC) patients] who were treated at Fudan University Shanghai Cancer Center. The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort. Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes. RESULTS: The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1% (47/465). The median overall survival (OS) in the mTNBC cohort was 27.2 months [95% confidence interval (CI), 24.4-30.2 months], which indicated a poor prognosis. The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed. Consistent molecular subtypes were maintained in 77.5% of the patients throughout disease progression with the mesenchymal-like (MES) subtype demonstrating a tendency for subtype transition and brain metastasis. Additionally, a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial. CONCLUSIONS: Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression. However, we emphasize the major importance of repeat pathologic confirmation of the MES subtype.

Development and Validation of a Low-Cost Drilling Model.

Background: Simulation models enable learners to have repeated practise at their own time, to master the psycho-motor and sensory acuity aspects of surgery and build their confidence in the procedure. The study aims to develop and evaluate the feasibility of a low-cost drilling model to train surgeons in the drilling task. The model targets three aspects of drilling - (1) Reduce plunge depth, (2) Ability to differentiate between bone and medullary canal and (3) Increase accuracy drilling in various angles. Methods: This cross-sectional study was conducted after obtaining ethics approval. We invited Consultants in the field of Orthopaedic or Hand Surgery to form the 'expert' group, and the 'novice' group consisted of participants who had no prior experience in bone drilling. We developed a drilling simulator model made from a polyvinyl chloride (PVC) pipe filled with liquid silicone. This model cost less than US$5. An electric Bosch drill (model GBM 10 RE) with a 1.4 mm K-wire 10 cm in length (6.5 cm outside the drill) was used for drilling. The main outcomes of the study were time taken for drilling, plunge depth, ability to penetrate the far cortex and accuracy. Results: Thirty-one participants were recruited into the study, of which 15 were experts and 16 were novices. The experts performed significantly better for plunge depth (t = -3.65, p = 0.0003) and accuracy (t = -2.07, p = 0.04). The experts required 20% less time to complete the drilling tasks, but it was not statistically significant (t = -0.79, p = 0.43). Conclusions: The low-cost drilling model could be useful in training Residents in the drilling task. It will allow Residents to practise independently at their own time and assess their own performance.

Calcification-associated molecular traits and therapeutic strategies in hormone receptor-positive HER2-negative breast cancer.

OBJECTIVE: Mammographic calcifications are a common feature of breast cancer, but their molecular characteristics and treatment implications in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer remain unclear. METHODS: We retrospectively collected mammography records of an HR+/HER2- breast cancer cohort (n = 316) with matched clinicopathological, genomic, transcriptomic, and metabolomic data. On the basis of mammographic images, we grouped tumors by calcification status into calcification-negative tumors, tumors with probably benign calcifications, tumors with calcification of low-moderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy. We then explored the molecular characteristics associated with each calcification status across multiple dimensions. RESULTS: Among the different statuses, tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores, estrogen receptor (ER) pathway activation, lipid metabolism, and sensitivity to endocrine therapy. Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes, elevated lymph node metastasis incidence, Ki-67 staining scores, genomic instability, cell cycle pathway activation, and may benefit from cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. CONCLUSIONS: Our research established links between tumor calcifications and molecular features, thus proposing potential precision treatment strategies for HR+/HER2- breast cancer.

Salvage of Failed Proximal Interphalangeal Arthroplasty with Vascularised Toe Joint Transfer: Report of Two Cases.

Failed implants of the proximal interphalangeal joint may result in bone and soft tissue deficits and joint instability with limited reliable options for reconstruction besides an arthrodesis procedure. The purpose of this report is to illustrate the use of vascularized second toe joint for salvage of failed, multi-operated proximal interphalangeal joint in two active patients. Pre-existing scars are used to define the approach and choice of donor site. Flow through anastomosis was performed on the finger digital artery. At final follow-up, the transplanted joints achieved 80-90 degrees of motion and the patients were able to return to their desired level of activities. The procedure is a good alternative for the fit patient wanting to achieve a stable finger with preservation of motion in catastrophic failure of prosthetic proximal interphalangeal joint arthroplasty.

Proximity-Guaranteed DNA Machine for Accurate Identification of Breast Cancer Extracellular Vesicles.

Breast cancer is one of the most diagnosed cancers worldwide. Precise diagnosis and subtyping have important significance for targeted therapy and prognosis prediction of breast cancer. Herein, we design a proximity-guaranteed DNA machine for accurate identification of breast cancer extracellular vesicles (EVs), which is beneficial to explore the subtype features of breast cancer. In our design, two proximity probes are located close on the same EV through specific recognition of coexisting surface biomarkers, thus being ligated with the help of click chemistry. Then, the ligated product initiates the operation of a DNA machine involving catalytic hairpin assembly and clusters of regularly interspaced short palindromic repeats (CRISPR)-Cas12a-mediated trans-cleavage, which finally generates a significant response that enables the identification of EVs expressing both biomarkers. Principle-of-proof studies are performed using EVs derived from the breast cancer cell line BT474 as the models, confirming the high sensitivity and specificity of the DNA machine. When further applied to clinical samples, the DNA machine is shown to be capable of not only distinguishing breast cancer patients with special subtypes but also realizing the tumor staging regarding the disease progression. Therefore, our work may provide new insights into the subtype-based diagnosis of breast cancer as well as identification of more potential therapeutic targets in the future.

Leaky gut, circulating immune complexes, arthralgia, and arthritis in IBD: coincidence or inevitability?

Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.

Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.

Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism.

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

Comparison of ICG-Guided Near-Infrared Fluorescence Imaging and Modified Inflation-Deflation Method in Identifying the Intersegmental Plane During Lung Segmentectomy of Infants.

BACKGROUND: The identification of the intersegmental plane (ISP) is a crucial step in segmentectomy for children with congenital pulmonary airway malformation (CPAM) due to complex anatomical variations. However, there is very limited literature available on this aspect specifically for infant. In this study, we compared the intravenous indocyanine green (ICG)-guided near-infrared fluorescence (NIRF) imaging method with the modified inflation-deflation method in terms of their perioperative characteristics and summarized our experience. METHODS: From June 2021 to November 2022, the data of 83 patients with CPAM who underwent segmentectomy by video-assisted thoracoscopic surgery were retrospectively reviewed. Twenty-eight patients underwent ICG-guided NIRF method, and 56 patients underwent the modified inflation-deflation method, characteristics and clinical outcomes were compared. RESULTS: The median age of the patients was 4.99 months (4.99 ± 1.51) with a mean body weight of 7.54 kg (7.54 ± 1.99). Both methods could accurately identify the ISP. The time taken to clearly display the ISP was shorter in ICG group than in the modified inflation-deflation group (0.18 ± 0.08 vs. 6.49 ± 1.67 min; P < 0.001), and the surgical duration (61.32 ± 14.28 vs. 88.18 ± 8.03 min; P < 0.001) were significantly shorter in the ICG group too. The two groups exhibited differences in the length of chest tube drainage (1.75 ± 1.24 vs. 2.36 ± 1.54 days; P = 0.072) and the length of hospital stay (4.61 ± 1.75 vs. 5.20 ± 3.07 days; P = 0.078), however, the differences were not statistically significant. There were no significant differences between the two groups in the blood lost and postoperative complications. At a follow-up of more than 1 year after operation, all patients had recovered well without recurrence. CONCLUSIONS: According to our experience, the ICG-guided NIRF method was safe and feasible for infants during thoracoscopic segmentectomy, it can quickly display the ISP and shorten the surgical duration compared with the modified inflation-deflation method.

UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

Comparison of safety and efficacy of different positions in percutaneous nephrolithotomy: a network meta-analysis.

OBJECTIVES: Various new positions for percutaneous nephrolithotomy (PCNL) were proposed to reduce the limitations of the traditional position. This study was aimed to evaluate the efficacy and safety of the different PCNL positions. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs) up to 18 April 2023. The authors collected five common surgical positions used for PCNL: oblique supine position (OSP), supine position (SP), flank position (FP), split-leg oblique supine/flank position (SLP), and prone position (PP). Paired and network meta-analysis were conducted to compare relevant outcomes, including complications, operative time, stone-free rates, hospital stay, and hemoglobin loss among these different positions. RESULTS: The study included 17 RCTs with a total of 1841 patients. The result demonstrated that SLP significantly outperformed in terms of decreasing operation time (FP vs SLP MD- MD-41.65; OSP vs SLP MD 28.97; PP vs SLP MD 34.94), hospital stay, and hemoglobin loss. Ranking probabilities showed SLP had highest stone-free rate. Prone position was more likely to occur complications than others. Based on SMAA model, the benefit-risk analysis suggested the SLP was the optimal position in PCNL. CONCLUSIONS: For PCNL, the split-leg, flank, supine, and OSPs are as secure as the prone position. Further RCTs are necessary to confirm the outstanding safety and efficacy of split-leg position. Besides, the position should be selected regard for the patient's demands, the surgeon's preference and learning curve.

The efficacy of extracorporeal shock wave combined with platelet rich plasma in the treatment of knee osteoarthritis with meniscus injury: A retrospective analysis.

Objective: To determine the efficacy of extracorporeal shock wave (ESW) combined with autologous platelet-rich plasma (PRP) therapy on knee osteoarthritis (KOA) with meniscus injury in terms of pain relief, functional outcome and complications. Methods: This is a retrospective observational study. Clinical data of 144 patients with KOA accompanied by medial meniscus injury, who received treatment in Jilin Provincial People's Hospital from March 2021 to December 2022, were retrospectively evaluated. A total of 128 patients (81 males and 47 females) were finally included in the study after screening. Of them, 45 patients received PRP treatment (PRP-group), 43 patients received ESW treatment (ESW-group), and 40 patients received ESW combined with PRP treatment (Combined-group). The relief of knee joint pain and functional improvement among three groups of patients were compared. Results: After treatment, visual analogue scale (VAS), Lequesne, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores of patients in the Combined-group were significantly lower than those in the other two groups (p<0.05). Combined ESW-PRP treatment was associated with significantly greater joint range of motion of patients compared to ESW and PRP alone (p<0.05). The total incidence of related complications in the Combined-group was lower compared to the other two groups (p<0.05). Conclusions: Compared with PRP or ESW treatment alone, ESW combined with PRP for KOA with meniscus injury can better alleviate pain, achieve faster functional recovery, and significantly reduce complications.

Integrated multiomic profiling of breast cancer in the Chinese population reveals patient stratification and therapeutic vulnerabilities.

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.

[Effect of Zuogui Jiangtang Jieyu Formula on intestinal flora and short-chain fatty acid metabolism in rats with diabetes mellitus complicated with depression].

This study aimed to investigate the regulatory effects of Zuogui Jiangtang Jieyu Formula(ZJJ) on the intestinal flora, short chain fatty acids(SCFAs), and neuroinflammation in rats with diabetes mellitus complicated depression(DD). The DD model was established in rats and model rats were randomly divided into a model group, a positive drug(metformin + fluoxetine) group, a ZJJ low-dose group, and a ZJJ high-dose group, with eight rats in each group. Another eight rats were assigned to the blank group. Subsequently, depressive-like behavior test was conducted on the rats, and cerebrospinal fluid samples were collected to measure pro-inflammatory cytokines [interleukin-1ß(IL-1ß), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α)]. Blood serum samples were collected to measure proteins related to the hypothalamic-pituitary-adrenal axis(HPA axis), including corticotropin-releasing hormone(CRH), adrenocorticotropic hormone(ACTH), and cortisol(CORT), as well as glucose metabolism. Gut contents were collected from each group for 16S rRNA sequencing analysis of intestinal flora and SCFAs sequencing. The results indicated that ZJJ not only improved glucose metabolism in DD rats(P<0.01) but also alleviated depressive-like behavior(P<0.05) and HPA axis hyperactivity(P<0.05 or P<0.01). Besides, it also improved the neuroinflammatory response in the brain, as evidenced by a significant reduction in pro-inflammatory cytokines in cerebrospinal fluid(P<0.05 or P<0.01). Additionally, ZJJ improved the intestinal flora, causing the intestinal flora in DD rats to resemble that of the blank group, characterized by an increased Firmicutes abundance. ZJJ significantly increased the levels of SCFAs(acetic acid, butyric acid, valeric acid, and isovaleric acid)(P<0.01). Therefore, it is deduced that ZJJ can effectively ameliorate intestinal flora dysbiosis, regulate SCFAs, and thereby improve both glucose metabolism disturbances and depressive-like behavior in DD.

Experimental treatment efficacy of dmrFABP5 on prostate cancer singly or in combination with drugs in use.

Enzalutamide is a drug used to treat prostate cancer (PC) and docetaxel is a drug for chemotherapeutic treatment of diverse cancer types, including PC. The effectiveness of these drugs in treating castration-resistant prostate cancer (CRPC) is poor and therefore CRPC is still largely incurable. However, the bio-inhibitor of fatty acid-binding protein 5 (FABP5), dmrFABP5, which is a mutant form of FABP5 incapable of binding to fatty acids, has been shown recently to be able to suppress the tumorigenicity and metastasis of cultured CRPC cells. The present study investigated the possible synergistic effect of dmrFABP5 combined with either enzalutamide or docetaxel on suppressing the tumorigenic properties of PC cells, including cell viability, migration, invasion and colony proliferation in soft agar. A highly significant synergistic inhibitory effect on these properties was observed when dmrFABP5 was used in combination with enzalutamide on androgen-responsive PC 22RV1 cells. Moreover, a highly significant synergistic inhibitory effect was also observed when dmrFABP5 was combined with docetaxel, and added to 22RV1 cells and to the highly malignant, androgen-receptor (AR)-negative Du145 cells. DmrFABP5 alone failed to produce any suppressive effect when added to the FABP5-negative cell line LNCaP, although enzalutamide could significantly suppress LNCaP cells when used as a single agent. These synergistic inhibitory effects of dmrFABP5 were produced by interrupting the FABP5-related signal transduction pathway in PC cells. Thus, dmrFABP5 appears to be not only a potential single therapeutic agent, but it may also be used in combination with existing drugs to suppress both AR-positive and AR-negative PC.

Efficacy of artificial intelligence in reducing miss rates of GI adenomas, polyps, and sessile serrated lesions: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: The aim of this study was to determine if utilization of artificial intelligence (AI) in the course of endoscopic procedures can significantly diminish both the adenoma miss rate (AMR) and the polyp miss rate (PMR) compared with standard endoscopy. METHODS: We performed an extensive search of various databases, encompassing PubMed, Embase, Cochrane Library, Web of Science, and Scopus, until June 2023. The search terms used were artificial intelligence, machine learning, deep learning, transfer machine learning, computer-assisted diagnosis, convolutional neural networks, gastrointestinal (GI) endoscopy, endoscopic image analysis, polyp, adenoma, and neoplasms. The main study aim was to explore the impact of AI on the AMR, PMR, and sessile serrated lesion miss rate. RESULTS: A total of 7 randomized controlled trials were included in this meta-analysis. Pooled AMR was markedly lower in the AI group versus the non-AI group (pooled relative risk [RR], .46; 95% confidence interval [CI], .36-.59; P < .001). PMR was also reduced in the AI group in contrast with the non-AI control (pooled RR, .43; 95% CI, .27-.69; P < .001). The results showed that AI decreased the miss rate of sessile serrated lesions (pooled RR, .43; 95% CI, .20 to .92; P < .05) and diminutive adenomas (pooled RR, .49; 95% CI, .26-.93) during endoscopy, but no significant effect was observed for advanced adenomas (pooled RR, .48; 95% CI, .17-1.37; P = .17). The average number of polyps (Hedges' g = -.486; 95% CI, -.697 to -.274; P = .000) and adenomas (Hedges' g = -.312; 95% CI, -.551 to -.074; P = .01) detected during the second procedure also favored AI. However, AI implementation did not lead to a prolonged withdrawal time (P > .05). CONCLUSIONS: This meta-analysis suggests that AI technology leads to significant reduction of miss rates for GI adenomas, polyps, and sessile serrated lesions during endoscopic surveillance. These results underscore the potential of AI to improve the accuracy and efficiency of GI endoscopic procedures.

Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.