Functional modification of gut bacteria for disease diagnosis and treatment.

Intestinal bacteria help keep humans healthy by regulating lipid and glucose metabolism as well as the immunological and neurological systems. Oral treatment using intestinal bacteria is limited by the high acidity of stomach fluids and the immune system's attack on foreign bacteria. Scientists have created coatings and workarounds to overcome these limitations and improve bacterial therapy. These preparations have demonstrated promising outcomes, with advances in synthetic biology and optogenetics improving their focused colonization and controlled release. Engineering bacteria preparations have become a revolutionary therapeutic approach that converts intestinal bacteria into cellular factories for medicinal chemical synthesis. The present paper discusses various aspects of engineering bacteria preparations, including wrapping materials, biomedical uses, and future developments.

DrugMetric: quantitative drug-likeness scoring based on chemical space distance.

The process of drug discovery is widely known to be lengthy and resource-intensive. Artificial Intelligence approaches bring hope for accelerating the identification of molecules with the necessary properties for drug development. Drug-likeness assessment is crucial for the virtual screening of candidate drugs. However, traditional methods like Quantitative Estimation of Drug-likeness (QED) struggle to distinguish between drug and non-drug molecules accurately. Additionally, some deep learning-based binary classification models heavily rely on selecting training negative sets. To address these challenges, we introduce a novel unsupervised learning framework called DrugMetric, an innovative framework for quantitatively assessing drug-likeness based on the chemical space distance. DrugMetric blends the powerful learning ability of variational autoencoders with the discriminative ability of the Gaussian Mixture Model. This synergy enables DrugMetric to identify significant differences in drug-likeness across different datasets effectively. Moreover, DrugMetric incorporates principles of ensemble learning to enhance its predictive capabilities. Upon testing over a variety of tasks and datasets, DrugMetric consistently showcases superior scoring and classification performance. It excels in quantifying drug-likeness and accurately distinguishing candidate drugs from non-drugs, surpassing traditional methods including QED. This work highlights DrugMetric as a practical tool for drug-likeness scoring, facilitating the acceleration of virtual drug screening, and has potential applications in other biochemical fields.

Microplastic pollution differences in freshwater river according to stream order: Insights from spatial distribution, annual load, and ecological assessment.

Microplastic (MP) pollution has become a pressing concern in global freshwater ecosystems because rivers serve as essential channels for the transport of terrestrial debris to the ocean. The current researches mostly focus on the large catchments, but the impact on the small catchments remains underexplored. In this study, we employed Strahler's stream order classification to delineate the catchment structure of the Beijiang River in South China. The distribution pattern of MP contamination and the factors influencing the distribution pattern, were assessed across the streams at different orders. We found that the Beijiang River was moderately polluted compare to other rivers in China, with an average MP abundance of 2.15 ± 1.65 items/L. MP abundance ranged from 3.17 to 1.45 items/L in the streams at different orders, and significantly decreased with increasing stream order (R2 = 0.93). This highlights the key role of small rivers as the channels for the transport of MPs from watersheds to main streams. The high abundance of PP and PE fibers, the high correlation between the stream order and the resin proportion (R2 = 0.89), and the significant correlation between MP abundance and proximity to urban centers (P = 0.02), indicated that MP pollution across the streams at different orders was predominantly influenced by anthropogenic activities, rather than natural environmental factors. By integrating MP data with hydrographic information, the annual MP loads for the streams at Orders 1 to Order 5 were estimated to be 4.63, 39.38, 204.63, 503.06, and 1137.88 tons/yr, respectively. Additionally, an ecological risk assessment indicates that MP pollution led to a low risk in the Beijiang River. Our findings deepen the understanding of MP pollution within freshwater river networks, and emphasize the crucial role of tributary systems in transporting MPs to main river channels.

Neoadjuvant BRAF and MEK inhibitor therapy elicits pathological complete response in stage IIIA non-small cell lung cancer harboring BRAF V600E mutation: A case report.

In recent years, significant improvement has been made in the management of non-small cell lung cancer (NSCLC), primarily driven by advances in targeted therapy and immunotherapy. Research on neoadjuvant targeted therapy has also experienced considerable development, primarily directed towards NSCLC harboring epidermal growth factor receptor or anaplastic lymphoma kinase mutations. Nevertheless, there remains a dearth of studies investigating neoadjuvant targeted therapy in the context of BRAF (V-Raf murine sarcoma viral oncogene homolog B) V600E mutant NSCLC. Herein, we describe the clinical trajectory of a stage IIIA NSCLC patient who underwent a two-month course of neoadjuvant targeted therapy comprising BRAF and MEK (mitogen-activated extracellular signal-regulated kinase) inhibitors prior to surgical intervention, and subsequent postoperative evaluation unveiled a pathological complete response. The case reported here indicates the efficacy and safety of combining BRAF and MEK inhibitors as neoadjuvant targeted therapy in BRAF V600E-mutant NSCLC and suggests the potential viability of such a therapeutic modality in improving treatment outcomes in this subset of NSCLC.

NIR-Remote Selectively Triggered Buprenorphine Hydrochloride Release from Microneedle Patches for the Treatment of Neuropathic Pain.

Neuropathic pain is a prevalent form of intermittent chronic pain, affecting approximately 7-10% of the global population. However, the current clinical administration methods, such as injection and oral administration, are mostly one-time administration, which cannot achieve accurate control of pain degree and drug dose. Herein, we developed near-infrared (NIR) light-responsive microneedle patches (MNPs) to spatiotemporally control the drug dose released to treat neuropathic pain according to the onset state. The mechanism of action utilizes upconversion nanoparticles to convert NIR light into visible and ultraviolet light. This conversion triggers the rapid rotation of the azobenzene molecular motor in the mesoporous material, enabling the on-demand controlled release of a drug dose. Additionally, MNs are used to overcome the barrier of the stratum corneum in a minimally invasive and painless manner, effectively promoting the transdermal penetration of drug molecules. The effectiveness of these patches has been demonstrated through significant results. Upon exposure to NIR light for five consecutive cycles, with each cycle lasting 30 s, the patches achieved a precise release of 318 µg of medication. In a mouse model, maximum pain relief was observed within 1 h of one cycle of NIR light exposure, with the effects lasting up to 6 h. The same level of precise treatment efficacy was maintained for subsequent pain episodes with similar light exposure. The NIR-controlled drugs precision-released MNPs provide a novel paradigm for the treatment of intermittent neuropathic pain.

Light-activated Nanocatalyst for Precise In-situ Antimicrobial Synthesis via Photoredox-Catalytic Click Reaction.

The excessive and prolonged use of antibiotics contributes to the emergence of drug-resistant S. aureus strains and potential dysbacteriosis-related diseases, necessitating the exploration of alternative therapeutic approaches. Herein, we present a light-activated nanocatalyst for synthesizing in-situ antimicrobials through photoredox-catalytic click reaction, achieving precise, site-directed elimination of S. aureus skin infections. Methylene blue (MB), a commercially available photosensitizer, was encapsulated within the CuII-based metal-organic framework, MOF-199, and further enveloped with Pluronic F-127 to create the light-responsive nanocatalyst MB@PMOF. Upon exposure to red light, MB participates in a photoredox-catalytic cycle, driven by the 1,3,5-benzenetricarboxylic carboxylate salts (BTC-) ligand presented in the structure of MOF-199. This light-activated MB then catalyzes the reduction of CuII to CuI through a single-electron transfer (SET) process, efficiently initiating the click reaction to form active antimicrobial agents under physiological conditions. Both in vitro and in vivo results demonstrated the effectiveness of MB@PMOF-catalyzed drug synthesis in inhibiting S. aureus, including their methicillin-resistant strains, thereby accelerating skin healing in severe bacterial infections. This study introduces a novel design paradigm for controlled, on-site drug synthesis, offering a promising alternative to realize precise treatment of bacterial infections without undesirable side effects.

MRI versus Dual-Energy CT in Local-Regional Staging of Gastric Cancer.

Background Preoperative local-regional tumor staging of gastric cancer (GC) is critical for appropriate treatment planning. The comparative accuracy of multiparametric MRI (mpMRI) versus dual-energy CT (DECT) for staging of GC is not known. Purpose To compare the diagnostic accuracy of personalized mpMRI with that of DECT for local-regional T and N staging in patients with GC receiving curative surgical intervention. Materials and Methods Patients with GC who underwent gastric mpMRI and DECT before gastrectomy with lymphadenectomy were eligible for this single-center prospective noninferiority study between November 2021 and September 2022. mpMRI comprised T2-weighted imaging, multiorientational zoomed diffusion-weighted imaging, and extradimensional volumetric interpolated breath-hold examination dynamic contrast-enhanced imaging. Dual-phase DECT images were reconstructed at 40 keV and standard 120 kVp-like images. Using gastrectomy specimens as the reference standard, the diagnostic accuracy of mpMRI and DECT for T and N staging was compared by six radiologists in a pairwise blinded manner. Interreader agreement was assessed using the weighted κ and Kendall W statistics. The McNemar test was used for head-to-head accuracy comparisons between DECT and mpMRI. Results This study included 202 participants (mean age, 62 years ± 11 [SD]; 145 male). The interreader agreement of the six readers for T and N staging of GC was excellent for both mpMRI (κ = 0.89 and 0.85, respectively) and DECT (κ = 0.86 and 0.84, respectively). Regardless of reader experience, higher accuracy was achieved with mpMRI than with DECT for both T (61%-77% vs 50%-64%; all P < .05) and N (54%-68% vs 51%-58%; P = .497-.005) staging, specifically T1 (83% vs 65%) and T4a (78% vs 68%) tumors and N1 (41% vs 24%) and N3 (64% vs 45%) nodules (all P < .05). Conclusion Personalized mpMRI was superior in T staging and noninferior or superior in N staging compared with DECT for patients with GC. Clinical trial registration no. NCT05508126 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Méndez and Martín-Garre in this issue.

TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1.

Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo. Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC.

The first structure of human Golm1 coiled coil domain reveals an unexpected tetramer and highlights its structural diversity.

Golgi membrane protein 1 (Golm1), a transmembrane protein with diverse subcellular localizations, has garnered significant attention in recent years due to its strong association with the development and progression of liver diseases and numerous cancers. Interestingly, although Golm1 is a membrane protein, the C-terminal of Golm1, which contains a coiled coil domain and a flexible acid region, can also be detected in the plasma of patients with various liver diseases. Notably, the coiled coil domain of serum Golm1 is postulated to play a pivotal role in physiological and pathological functions. However, little is currently known about the structure of this coiled coil domain and the full-length protein, which may limit our understanding of Golm1. Therefore, this study aims to address this gap in knowledge and reports the first crystal structure of the coiled coil domain of Golm1 at a resolution of 2.28 Å. Meanwhile, we have also confirmed that the Golm1 coiled coil domain in solution can form tetramer. Our results reveal that Golm1 can form a novel tetrameric structure that differs from the previous reported dimeric structure Golm1 could assemble, which may provide novel insights into the diversity of physiological functions and pathological roles.

USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition.

Ripretinib, a broad-spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth-line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome-ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5-MDH2 axis to counteract ripretinib resistance in GIST.

Changes in visual performance after implantation of different intraocular lenses.

AIM: To evaluate the trending visual performance of different intraocular lenses (IOLs) over time after implantation. METHODS: Ninety-one patients received cataract surgery with implantations of monofocal (Mon) IOLs, segmental refractive (SegRef) IOLs, diffractive (Dif) IOLs, and extended-depth-of-focus (EDoF) IOLs were included. The aberrations and optical quality collected with iTrace and OQAS within postoperative 6mo were followed and compared. RESULTS: Most of the visual parameters improved over the postoperative 6mo. The postoperative visual acuity (POVA) of the Mon IOL, SegRef IOL, and EDoF IOL groups achieved relative stability in earlier states compared with the Dif IOL group. Nevertheless, the overall visual performance of the 3 IOLs continued to upturn in small extents within the postoperative 6mo. The optical quality initially improved in the EDoF IOL group, then in the Mon IOL, SegRef IOL, and Dif IOL groups. POVA and objective visual performance of the Mon IOL and EDoF IOL groups, as well as POVA and visual quality of the Dif IOL group, improved in the postoperative 1mo and stabilized. Within the postoperative 6mo, gradual improvements were observed in the visual acuity and objective visual performance of the SegRef IOL group, as well as in the postoperative optical quality of the Dif IOL group. CONCLUSION: The visual performance is different among eyes implanted with different IOLs. The findings of the current study provide a potential reference for ophthalmologists to choose suitable IOLs for cataract patients in a personalized solution.

GSDMB involvement in the pathogenesis of abdominal aortic aneurysm through regulation of macrophage non-canonical pyroptosis.

Abdominal aortic aneurysm (AAA) is a dangerous condition affecting the aorta. Macrophage pyroptosis, phenotypic transformation, and apoptosis of aortic smooth muscle cells (ASMCs) are pivotal mechanisms in AAA pathogenesis. This study explores how Gasdermin B (GSDMB) regulates macrophage non-canonical pyroptosis and its impact on the phenotypic transformation and apoptosis of ASMCs, thereby unveiling the role of GSDMB in AAA pathogenesis. Immunofluorescence analysis was used to assess the expression levels and localization of GSDMB, cysteinyl aspartate-specific protease-4 (Caspase-4), and N-terminal of cleaved GSDMD (N-GSDMD) in AAA tissues. A cell model that mimics macrophage non-canonical pyroptosis was established by treating THP-1 cells with lipopolysaccharide (LPS). THP-1 cells with reduced or increased GSDMB were generated using small interfering RNA (siRNA) or plasmids. Co-culture experiments involving THP-1 cells and HASMCs were conducted to explore the impact of GSDMB on HASMCs. The mitochondrial reactive oxygen species (mtROS) scavenger Mito-TEMPO lowered mtROS levels in THP-1 cells. Our findings revealed that GSDMB was significantly upregulated in AAA macrophages, which was accompanied by robust non-canonical pyroptosis. THP-1 cells showed non-canonical pyroptosis in response to LPS, which was accompanied by an increase in GSDMB. Further research demonstrated that altering GSDMB, either by knockdown or overexpression, can affect macrophage non-canonical pyroptosis as well as the phenotypic transformation and apoptosis of HASMCs. LPS-induced non-canonical pyroptosis in THP-1 cells was associated with an increase in mtROS, whereas Mito-TEMPO effectively decreased non-canonical pyroptosis and the expression of GSDMB. These findings suggest that GSDMB plays a role in AAA macrophage non-canonical pyroptosis, which influences the phenotypic transformation and apoptosis of HASMCs. The mtROS-Dynamin-Related Protein 1 (Drp1) axis is likely to regulate the GSDMB-mediated non-canonical pyroptosis.

Visible light-induced chemoselective 1,2-diheteroarylation of alkenes.

Visible-light photocatalysis has evolved as a powerful technique to enable controllable radical reactions. Exploring unique photocatalytic mode for obtaining new chemoselectivity and product diversity is of great significance. Herein, we present a photo-induced chemoselective 1,2-diheteroarylation of unactivated alkenes utilizing halopyridines and quinolines. The ring-fused azaarenes serve as not only substrate, but also potential precursors for halogen-atom abstraction for pyridyl radical generation in this photocatalysis. As a complement to metal catalysis, this photo-induced radical process with mild and redox neutral conditions assembles two different heteroaryl groups into alkenes regioselectively and contribute to broad substrates scope. The obtained products containing aza-arene units permit various further diversifications, demonstrating the synthetic utility of this protocol. We anticipate that this protocol will trigger the further advancement of photo-induced alkyl/aryl halides activation.

Regioselective α-Phosphonylation of Unprotected Alicyclic Amines.

Unprotected alicyclic amines undergo α-C-H bond phosphonylation via a two-stage one-pot process involving the oxidation of amine-derived lithium amides with simple ketone oxidants, generating transient imines which are then captured with phosphites or phosphine oxides. Amines with an existing α-substituent undergo regioselective α'-phosphonylation. Amine α-arylation and α'-phosphonylation can be combined, generating a difunctionalized product in a single operation.

Chemoinformatics Insights on Molecular Jackhammers and Cancer Cells.

One of the most challenging tasks in modern medicine is to find novel efficient cancer therapeutic methods with minimal side effects. The recent discovery of several classes of organic molecules known as "molecular jackhammers" is a promising development in this direction. It is known that these molecules can directly target and eliminate cancer cells with no impact on healthy tissues. However, the underlying microscopic picture remains poorly understood. We present a study that utilizes theoretical analysis together with experimental measurements to clarify the microscopic aspects of jackhammers' anticancer activities. Our physical-chemical approach combines statistical analysis with chemoinformatics methods to design and optimize molecular jackhammers. By correlating specific physical-chemical properties of these molecules with their abilities to kill cancer cells, several important structural features are identified and discussed. Although our theoretical analysis enhances understanding of the molecular interactions of jackhammers, it also highlights the need for further research to comprehensively elucidate their mechanisms and to develop a robust physical-chemical framework for the rational design of targeted anticancer drugs.

Electrothermal mineralization of per- and polyfluoroalkyl substances for soil remediation.

Per- and polyfluoroalkyl substances (PFAS) are persistent and bioaccumulative pollutants that can easily accumulate in soil, posing a threat to environment and human health. Current PFAS degradation processes often suffer from low efficiency, high energy and water consumption, or lack of generality. Here, we develop a rapid electrothermal mineralization (REM) process to remediate PFAS-contaminated soil. With environmentally compatible biochar as the conductive additive, the soil temperature increases to >1000 °C within seconds by current pulse input, converting PFAS to calcium fluoride with inherent calcium compounds in soil. This process is applicable for remediating various PFAS contaminants in soil, with high removal efficiencies ( >99%) and mineralization ratios ( >90%). While retaining soil particle size, composition, water infiltration rate, and cation exchange capacity, REM facilitates an increase of exchangeable nutrient supply and arthropod survival in soil, rendering it superior to the time-consuming calcination approach that severely degrades soil properties. REM is scaled up to remediate soil at two kilograms per batch and promising for large-scale, on-site soil remediation. Life-cycle assessment and techno-economic analysis demonstrate REM as an environmentally friendly and economic process, with a significant reduction of energy consumption, greenhouse gas emission, water consumption, and operation cost, when compared to existing soil remediation practices.

Causal relationships between immune cell phenotypes and lung adenocarcinoma: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD. METHODS: A bidirectional two-sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave-one-out analyses were performed to validate the reliability of our study. RESULTS: A total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD-CD38br cells, CD4+ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes. CONCLUSION: Our study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research.

Can proximal gastrectomy with double-tract reconstruction replace total gastrectomy? a meta-analysis of randomized controlled trials and propensity score-matched studies.

BACKGROUND: According to the 5th edition of the Japanese Guidelines for the Treatment of Gastric Cancer, proximal gastrectomy is recommended for patients with early upper gastric cancer who can retain the distal half of the residual stomach after R0 resection. However, a large number of recent clinical studies suggest that surgical indications for proximal gastrectomy in the guidelines may be too narrow. Therefore, this meta-analysis included patients with early and advanced gastric cancer and compared short- and long-term postoperative outcomes between the two groups. At the same time, we only had high-quality clinical studies such as propensity score-matched studies and randomized controlled trials, which made our research more authentic and credible. METHODS: Data were retrieved from PubMed, EMBASE, Medline, and Cochrane Library up to June 2023, and included treatment outcomes after proximal gastrectomy with double-tract reconstruction and total gastrectomy with Roux-en-Y reconstruction. The primary results were Early-phase complications(Anastomotic leakage, Anastomotic bleeding, Abdominal abscess, Abdominal infection, Pulmonary infection, Incision infection, Intestinal obstruction, Dumping syndrome, Pancreatic fistula), Late-phase complications(Intestinal obstruction, Anastomosis stricture, Dumping syndrome, Reoperation, Internal hernia, Incidence of endoscopic gastroesophageal reflux), Serious complications (≥ Grade III C-D score), Quality of life[Gastroesophageal reflux symptom evaluation (Visick score)(≥ III), Los Angeles classification(C or D)], Nutritional status(Hemoglobin, Receipt of vitamin B12 supplementation), Oncologic Outcomes(The 5-year overall survival rates). Secondary outcomes were surgical outcomes (Operative time, Estimated blood loss, Postoperative hospital stay, Number of harvested lymph nodes, Gas-passing, Postoperative mortality).The Cochrane risk-of-bias tool and Newcastle‒Ottawa scale were used to assess the quality of the included studies. RESULTS: After screening, 11 studies were finally included, including 1154 patients. Results from the combined literature showed that total gastrectomy had a significant advantage over proximal gastrectomy with double-tract reconstruction in mean operating time (MD = 4.92, 95% CI: 0.22∼9.61 P = 0.04). However, meta-analysis results showed that Hemoglobin (MD = 7.12, 95% CI:2.40∼11.84, P = 0.003) and Receipt of vitamin B12 supplementation (OR = 0.12, 95% CI:0.05∼0.26, P < 0.00001) in the proximal gastrectomy with double-tract reconstruction group were better than those in the total gastrectomy with Roux-en-Y reconstruction group. There is no significant difference between the proximal gastrectomy with double-tract reconstruction and the total gastrectomy with Roux-en-Y reconstruction group in Early-phase complications(OR = 1.14,95% CI:0.79∼1.64, P = 0.50), Late-phase complications(OR = 1.37,95% CI:0.78∼2.39, P = 0.27), Gastroesophageal reflux symptom evaluation (Visick score)(≥ III)(OR = 0.94,95% CI:0.14∼1.07 P = 0.07), Los Angeles classification(C or D)(OR = 0.33,95% CI:0.01∼8.21, P = 0.50), the 5-year overall survival rates (HR = 1.01, 95% CI: 0.83 ~ 1.23, P = 0.89). CONCLUSION: Proximal gastrectomy with double-tract anastomosis is a safe and feasible treatment for upper gastric carcinoma. However, the operating time was slightly longer in the proximal gastrectomy with double-tract group compared to the total gastrectomy with Roux-en-Y group. The two groups were comparable to the total gastrectomy with Roux-en-Y group in terms of serious complications (≥ Grade III C-D score), early-phase complications, late-phase complications, and quality of life. Although the scope of proximal gastrectomy is smaller than that of total gastrectomy, it does not affect the 5-year survival rate, indicating good tumor outcomes for patients. Compared to total gastrectomy with Roux-en-Y group, proximal gastrectomy with double-tract reconstruction had higher hemoglobin levels, lower probability of vitamin B12 supplementation, and better long-term efficacy. In conclusion, proximal gastrectomy with double-tract reconstruction is considered one of the more rational surgical approaches for upper gastric cancer.

Application of machine learning in a rodent malaria model for rapid, accurate, and consistent parasite counts.

Rodent malaria models serve as important preclinical antimalarial and vaccine testing tools. Evaluating treatment outcomes in these models often requires manually counting parasite-infected red blood cells (iRBCs), a time-consuming process, which can be inconsistent between individuals and labs. We have developed an easy-to-use machine learning (ML)-based software, Malaria Screener R, to expedite and standardize such studies by automating the counting of Plasmodium iRBCs in rodents. This software can process Giemsa-stained blood smear images captured by any camera-equipped microscope. It features an intuitive graphical user interface that facilitates image processing and visualization of the results. The software has been developed as a desktop application that processes images on standard Windows and Mac OS computers. A previous ML model created by the authors designed to count P. falciparum -infected human RBCs did not perform well counting Plasmodium -infected mouse RBCs. We leveraged that model by loading the pre-trained weights and training the algorithm with newly collected data to target P. yoelii and P. berghei mouse iRBCs. This new model reliably measured both P. yoelii and P. berghei parasitemia (R 2 = 0.9916). Additional rounds of training data to incorporate variances due to length of Giemsa staining, microscopes etc, have produced a generalizable model, meeting WHO Competency Level 1 for the sub-category of parasite counting using independent microscopes. Reliable, automated analyses of blood-stage parasitemia will facilitate rapid and consistent evaluation of novel vaccines and antimalarials across labs in an easily accessible in vivo malaria model.

A Microfluidic Chip-Based Automated System for Whole-Course Monitoring the Drug Responses of Organoids.

Tumor patients-derived organoids, as a promising preclinical prediction model, have been utilized to evaluate ex vivo drug responses for formulating optimal therapeutic strategies. Detecting adenosine triphosphate (ATP) has been widely used in existing organoid-based drug response tests. However, all commercial ATP detection kits containing the cell lysis procedure can only be applied for single time point ATP detection, resulting in the neglect of dynamic ATP variations in living cells. Meanwhile, due to the limited number of viable organoids from a single patient, it is impractical to exhaustively test all potential time points in search of optimal ones. In this work, a multifunctional microfluidic chip was developed to perform all procedures of organoid-based drug response tests, including establishment, culturing, drug treatment, and ATP monitoring of organoids. An ATP sensor was developed to facilitate the first successful attempt on whole-course monitoring the growth status of fragile organoids. To realize a clinically applicable automatic system for the drug testing of lung cancer, a microfluidic chip based automated system was developed to perform entire organoid-based drug response test, bridging the gap between laboratorial manipulation and clinical practices, as it outperformed previous methods by improving data repeatability, eliminating human error/sample loss, and more importantly, providing a more accurate and comprehensive evaluation of drug effects.