A Crucial Role of Adenosine Deaminase in Regulating Gluconeogenesis in mice.

Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine to inosine and regulates adenosine concentration. ADA ubiquitously expresses in various tissues to mediate adenosine receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus (T2DM). Here we show that elevated plasma ADA activity is a compensated response to high level of adenosine in T2DM and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA can reduces adenosine levels and decreases hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat-STZ diabetic mice. Mechanistically, ADA catabolizes adenosine and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.

Individual and mixture analyses of the associations of phenols and phthalates with lung function among US adults.

The effects of endocrine disruptors including phenols and phthalates on adult lung function remain unclear. In the present study, data from 2007-2012 National Health and Nutrition Examination Survey (NHANES) were extracted, and 4338 participants were included in the final analyses. The associations of three phenols and four phthalate metabolites with six lung function parameters were investigated. In generalized linear regression models (GLM) and restricted cubic spline (RCS) analyses, bisphenol A (BPA) was associated with decreased forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), and 2,5-dichlorophenol (DCP) was associated with reduced FEV1, FVC and peak expiratory flow rate (PEF), and increased prevalence of restrictive lung function (RLF) in adults. Furthermore, weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models demonstrated that mixed exposures to phenols and phthalates were linked to reduced FEV1, FVC and PEF and increased prevalence of RLF, and these associations were mainly driven by BPA and 2,5-DCP. In conclusion, mixed exposure to phenols and phthalates was linked to compromised and a restrictive pattern of lung function. The mechanisms of the effects of phenol and phthalate exposures on lung function and respiratory diseases need to be further investigated.

Independent and Combined Associations of Physical Activity and Screen Time With Biomarkers of Inflammation in Children and Adolescents With Overweight/Obesity.

PURPOSE: Inflammation regulation is important for obesity management and prevention of obesity-related diseases. This cross-sectional study aimed to analyze the independent and combined associations of physical activity and screen time with biomarkers of inflammation in children and adolescents with overweight/obesity. METHOD: A total of 1289 children and adolescents with overweight/obesity were included from the 2015 to 2018 National Health and Nutrition Examination Survey. Multivariable linear regressions were conducted for the association analyses. RESULTS: For the independent associations, a negative dose-dependent relationship was demonstrated between physical activity and inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) in adolescents with overweight/obesity (P < .001) but not children; screen time was not associated with hsCRP in both children and adolescents. No significant association was found between physical activity or screen time with other inflammatory biomarkers. For the combined associations, there was an interaction between physical activity and screen time on hsCRP in adolescents with overweight/obesity (P = .014). In addition, the negative association between physical activity and hsCRP was greater in boys compared with girls and in Hispanic and non-Hispanic Black individuals compared with non-Hispanic White individuals. CONCLUSION: This study demonstrated a combined association of physical activity and screen time with inflammatory biomarker hsCRP in adolescents with overweight/obesity.

Safety and efficacy of Yaobitong capsules for lumbar disc herniation: A multicenter, randomized, double-blinded, parallel, positive-controlled clinical trial.

BACKGROUND: Lumbar disc herniation (LDH) is one of the most common diseases and is a global medical and socioeconomic problem characterized by leg or back pain, weakness in the lower extremities and paresthesia. OBJECTIVES: A multicenter, randomized, double-blinded, parallel, positive-controlled clinical trial was conducted to evaluate the efficacy and safety of Yaobitong capsules (YBT) for LDH. MATERIAL AND METHODS: Patients (n = 479) were recruited and randomized into YBT and Jingyaokang capsule (JYK) groups (the positive control), and received YBT or JYK at a dose of 3 capsules 3 times per day after a meal for 30 days. The primary efficacy outcome was the Oswestry Disability Index (ODI), with the visual analogue scale (VAS) used as the secondary efficacy outcome. The adverse events and adverse reactions were also evaluated. RESULTS: There was no significant difference in baseline characteristics between YBT (n = 358) and JYK groups (n = 120), and no difference was observed between groups for mean ODI score at day 0 (p = 0.064) or day 7 (p = 0.196), but there were differences at days 14, 21 and 30 (p < 0.001). The YBT showed more decline from baseline, and the decreased ODI score was substantially different from JYK (p < 0.001). The differences in decreased VAS scores between YBT and JYK were also significant at each time point (days 7, 14, 21, and 30), with better scores in the YBT group than in the JYK group (p < 0.001). In terms of safety, there was no obvious disparity in adverse events or adverse reactions between the 2 groups (p > 0.05). CONCLUSIONS: Yaobitong was better than JYK for LDH treatment, with no significant difference in safety. The study suggests that YBT is a promising and effective treatment for LDH.

Neutrophil Extracellular Traps in Breast Cancer: Roles in Metastasis and Beyond.

Despite advances in the treatment of breast cancer, the disease continues to exhibit high global morbidity and mortality. The importance of neutrophils in cancer development has been increasingly recognized. Neutrophil extracellular traps (NETs) are web-like structures released into the extracellular space by activated neutrophils, serving as a potential antimicrobial mechanism for capturing and eliminating microorganisms. The roles played by NETs in cancer development have been a subject of intense research in the last decade. In breast cancer, current evidence suggests that NETs are involved in various stages of cancer development, particularly during metastasis. In this review, we try to provide an updated overview of the roles played by NETs in breast cancer metastasis. These include: 1) facilitating systemic dissemination of cancer cells; 2) promoting cancer-associated inflammation; 3) facilitating cancer-associated thrombosis; 4) facilitating pre-metastatic niche formation; and 5) awakening dormant cancer cells. The translational implications of NETs in breast cancer treatment are also discussed. Understanding the relationship between NETs and breast cancer metastasis is expected to provide important insights for developing new therapeutic strategies for breast cancer patients.

Cytosolic DNA sensors activation of human astrocytes inhibits herpes simplex virus through IRF1 induction.

Introduction: While astrocytes participate in the CNS innate immunity against herpes simplex virus type 1 (HSV-1) infection, they are the major target for the virus. Therefore, it is of importance to understand the interplay between the astrocyte-mediated immunity and HSV-1 infection. Methods: Both primary human astrocytes and the astrocyte line (U373) were used in this study. RT-qPCR and Western blot assay were used to measure IFNs, the antiviral IFN-stimulated genes (ISGs), IFN regulatory factors (IRFs) and HSV-1 DNA. IRF1 knockout or knockdown was performed with CRISPR/Cas9 and siRNA transfection techniques. Results: Poly(dA:dT) could inhibit HSV-1 replication and induce IFN-ß/IFN-λs production in human astrocytes. Poly(dA:dT) treatment of astrocytes also induced the expression of the antiviral ISGs (Viperin, ISG56 and MxA). Among IRFs members examined, poly(dA:dT) selectively unregulated IRF1 and IRF9, particularly IRF1 in human astrocytes. The inductive effects of poly(dA:dT) on IFNs and ISGs were diminished in the IRF1 knockout cells. In addition, IRF1 knockout attenuated poly(dA:dT)-mediated HSV-1 inhibition in the cells. Conclusion: The DNA sensors activation induces astrocyte intracellular innate immunity against HSV-1. Therefore, targeting the DNA sensors has potential for immune activation-based HSV-1 therapy.

Hexagonal Bipyramidal Mn3Ge5 Cluster and Its One-Dimensional Ferrimagnetic Sandwich Nanowire: Mn3Ge3 Rings as Structural Motifs.

Bipyramidal structures featuring planar rings serve as potential building blocks for one-dimensional (1D) nanostructures. Pure Ge atoms typically prefer to form three-dimensional rather than planar structures. Although a few-metal-doped bipyramids with pure Ge planar rings are predicted for constructing Ge-based 1D nanostructures, there is limited knowledge about those with both Ge and doped atoms on the same planar rings. Here, we report a hexagonal bipyramidal Mn3Ge5 cluster containing a Mn3Ge3 six-membered ring with the potential to construct a 1D germanium-based nanostructure. We investigated the structures and properties of Mn3Ge5-/0 using anion photoelectron spectroscopy and theoretical calculations. Mn3Ge5- has a C3v symmetric distorted hexagonal bipyramidal structure, while Mn3Ge5 has a C2v symmetric hexagonal bipyramidal structure. Chemical bonding analyses show that Mn3Ge5- could be considered as a [Mn3]V[Ge5]6- complex. First-principles calculations indicate that Mn3Ge5 may be used to construct a 1D ferrimagnetic [Mn3Ge5]∞ nanostructure.

[Charcoal-frying process and quality markers of Sanguisorbae Radix based on hemostatic effect].

Studies have reported that the hemostatic effect of Sanguisorbae Radix(SR) is significantly enhanced after processing with charcoal. However, the standard components(tannins and gallic acid) specified in the Chinese Pharmacopeia decrease in charcoal-fried Sanguisorbae Radix(CSR), which is contrast to the enhancement of the hemostatic effect. Therefore, this study aimed to optimize the charcoal-frying process of SR based on its hemostatic efficacy and comprehensively analyze the components of SR and its processed products, thus exploring the material basis for the hemostatic effect. The results indicated that SR processed at 250 ℃ for 14 min(14-min CSR) not only complied with the description in the Chinese Pharmacopeia but also demonstrated improved blood-coagulating and blood-adsorbing effects compared with raw SR(P<0.05). Moroever, 14-min CSR reduced the bleeding time in the rat models of tail snipping, liver bleeding, and muscle injury, surpassing both raw and excessively fried SR(16 min processed) as well as tranexamic acid(P<0.05). Ellagitannin, ellagic acid, methyl gallate, pyrogallic acid, protocatechuic acid, Mg, Ca, Mn, Cu, and Zn contributed to the hemostatic effect of CSR over SR. Among these substances, ellagitannin, ellagic acid, Mg, and Ca had high content in the 14 min CSR, reaching(106.73±14.87),(34.86±4.43),(2.81±0.23), and(1.21±0.23) mg·g~(-1), respectively. Additionally, the color difference value(ΔE~*ab) of SR processed to different extents was correlated with the content of the aforementioned hemostatic substances. In summary, this study optimized the charcoal-frying process as 250 ℃ for 14 min for SR based on its hemostatic effect. Furthermore, ellagic acid and/or the powder chromaticity are proposed as indicators for the processing and quality control of CSR.

Prevalence and outcomes of atrial fibrillation in patients suffering prostate cancer: a national analysis in the United States.

Purpose: Although the adverse effects of atrial fibrillation (AF) on cancers have been well reported, the relationship between the AF and the adverse outcomes in prostate cancer (PC) remains inconclusive. This study aimed to explore the prevalence of AF and evaluate the relationship between AF and clinical outcomes in PC patients. Methods: Patients diagnosed with PC between 2008 and 2017 were identified from the National Inpatient Sample database. The trends in AF prevalence were compared among PC patients and their subgroups. Multivariable regression models were used to assess the associations between AF and in-hospital mortality, length of hospital stay, total cost, and other clinical outcomes. Results: 256,239 PC hospitalizations were identified; 41,356 (83.8%) had no AF and 214,883 (16.2%) had AF. AF prevalence increased from 14.0% in 2008 to 20.1% in 2017 (P < .001). In-hospital mortality in PC inpatients with AF increased from 5.1% in 2008 to 8.1% in 2017 (P < .001). AF was associated with adverse clinical outcomes, such as in-hospital mortality, congestive heart failure, pulmonary circulation disorders, renal failure, fluid and electrolyte disorders, cardiogenic shock, higher total cost, and longer length of hospital stay. Conclusions: The prevalence of AF among inpatients with PC increased from 2008 to 2017. AF was associated with poor prognosis and higher health resource utilization. Better management strategies for patients with comorbid PC and AF, particularly in older individuals, are required.

Gestational diabetes mellitus enhances cobalt placental transfer efficiency between mother and infant.

Background: The fetal stage is pivotal for growth and development, making it susceptible to the adverse effects of prenatal metal(loid)s exposure. This study evaluated the influence of gestational diabetes mellitus (GDM) on the placental transfer efficiency (PTE) of metal(loid)s and thus assessed the associated risks of prenatal metal(loid)s exposure.Materials and method: Designed as a case-control study, it incorporated 114 pregnant participants: 65 without complications and 49 diagnosed with GDM. We utilized inductively coupled plasma mass spectrometry to quantify seven metal(loid)s - manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), gallium (Ga), arsenic (As), and cadmium (Cd) - in both maternal venous blood and umbilical cord blood.Result: We compared metal(loid)s concentrations and their PTE in the maternal and cord blood between the two groups. Notably, Cu, Ga, As, and Co levels in the umbilical cord blood of the GDM group (657.9 ± 167.2 µg/L, 1.23 ± 0.34 µg/L, 5.19 ± 2.58 µg/L, 1.09 ± 2.03 µg/L) surpassed those of the control group, with PTE of Co showing a marked increase in GDM group (568.8 ± 150.4 µg/L, 1.05 ± 0.31 µg/L, 4.09 ± 2.54 µg/L, 0.47 ± 0.91 µg/L), with PTE of Co showing a marked increase in GDM group (p < 0.05). The PTE of Ni exhibited a reduction in the GDM group relative to the control group, yet this decrease did not reach statistical significance.Conclusion: This study indicates that GDM can influence the placental transfer efficiency of certain metal(loid)s, leading to higher concentrations of Co, Cu, Ga, and As in the umbilical cord blood of the GDM group. The marked increase in the PTE of Co suggests a potential link to placental abnormal angiogenesis due to GDM.

The Causal Relationship between Plasma Myeloperoxidase Levels and Respiratory Tract Infections: A Bidirectional Mendelian Randomization Study.

Background: Observational researches reported the underlying correlation of plasma myeloperoxidase (MPO) concentration with respiratory tract infections (RTIs), but their causality remained unclear. Here, we examined the cause-effect relation between plasma MPO levels and RTIs. Materials and Methods: Datasets of plasma MPO levels were from the Folkersen et al. study (n = 21,758) and INTERVAL study (n = 3,301). Summarized data for upper respiratory tract infection (URTI) (2,795 cases and 483,689 controls) and lower respiratory tract infection (LRTI) in the intensive care unit (ICU) (585 cases and 430,780 controls) were from the UK Biobank database. The primary method for Mendelian randomization (MR) analysis was the inverse variance weighted approach, with MR-Egger and weighted median methods as supplements. Cochrane's Q test, MR-Egger intercept test, MR pleiotropy residual sum and outliers global test, funnel plots, and leave-one-out analysis were used for sensitivity analysis. Results: We found that plasma MPO levels were positively associated with URTI (odds ratio (OR) = 1.135; 95% confidence interval (CI) = 1.011-1.274; P=0.032) and LRTI (ICU) (OR = 1.323; 95% CI = 1.006-1.739; P=0.045). The consistent impact direction is shown when additional plasma MPO level genome-wide association study datasets are used (URTI: OR = 1.158; 95% CI = 1.072-1.251; P < 0.001; LRTI (ICU): OR = 1.216; 95% CI = 1.020-1.450; P=0.030). There was no evidence of a causal effect of URTI and LRTI (ICU) on plasma MPO concentration in the reverse analysis (P > 0.050). The sensitivity analysis revealed no violations of MR presumptions. Conclusions: Plasma MPO levels may causally affect the risks of URTI and LRTI (ICU). In contrast, the causal role of URTI and LRTI (ICU) on plasma MPO concentration was not supported in our MR analysis. Further studies are needed to identify the relationship between RTIs and plasma MPO levels.

Dysregulated Ribosome Biogenesis Is a Targetable Vulnerability in Triple-Negative Breast Cancer: MRPS27 as a Key Mediator of the Stemness-inhibitory Effect of Lovastatin.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.

Combined therapy of dabrafenib and an anti-HER2 antibody-drug conjugate for advanced BRAF-mutant melanoma.

BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma. METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy. RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway. CONCLUSION: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.

Successful management of Mycobacterium abscessus pneumonia in a 53-day-old immunocompetent infant.

Pulmonary infection due to Mycobacterium abscessus complex (MABC) usually occurs in children with underlying risk factors including cystic fibrosis (CF), chronic lung disease, and immunocompromised status, but rarely in immunocompetent children without underlying lung disease, especially in infants. We present a case of MABC pulmonary disease (MABC-PD) in an otherwise healthy 53-day-old male infant with one week of cough and respiratory distress. Computed tomography showed multiple masses across both lungs. Isolated mycobacteria from his bronchoalveolar lavage fluid were identified as MABC. We describe our complete evaluation, including immunodeficiency evaluation incorporating whole exome sequencing and our therapeutic process given complicated susceptibility pattern of the M. abscessus isolate, and review literature for MABC-PD in immunocompetent children. The infant was successfully treated through prolonged treatment with parenteral Amikacin, Cefoxitin, Linezolid, and Clarithromycin, combined with inhaled Amikacin.

Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia.

In the face of escalating metabolic disease prevalence, largely driven by modern lifestyle factors, this study addresses the critical need for novel therapeutic approaches. We have identified the sodium-coupled citrate transporter (NaCT or SLC13A5) as a target for intervention. Utilizing rational drug design, we developed a new class of SLC13A5 inhibitors, anchored by the hydroxysuccinic acid scaffold, refining the structure of PF-06649298. Among these, LBA-3 emerged as a standout compound, exhibiting remarkable potency with an IC50 value of 67 nM, significantly improving upon PF-06649298. In vitro assays demonstrated LBA-3's efficacy in reducing triglyceride levels in OPA-induced HepG2 cells. Moreover, LBA-3 displayed superior pharmacokinetic properties and effectively lowered triglyceride and total cholesterol levels in diverse mouse models (PCN-stimulated and starvation-induced), without detectable toxicity. These findings not only spotlight LBA-3 as a promising candidate for hyperlipidemia treatment but also exemplify the potential of targeted molecular design in advancing metabolic disorder therapeutics.

A Comprehensive Review on Synergy of Multi-Modal Data and AI Technologies in Medical Diagnosis.

Disease diagnosis represents a critical and arduous endeavor within the medical field. Artificial intelligence (AI) techniques, spanning from machine learning and deep learning to large model paradigms, stand poised to significantly augment physicians in rendering more evidence-based decisions, thus presenting a pioneering solution for clinical practice. Traditionally, the amalgamation of diverse medical data modalities (e.g., image, text, speech, genetic data, physiological signals) is imperative to facilitate a comprehensive disease analysis, a topic of burgeoning interest among both researchers and clinicians in recent times. Hence, there exists a pressing need to synthesize the latest strides in multi-modal data and AI technologies in the realm of medical diagnosis. In this paper, we narrow our focus to five specific disorders (Alzheimer's disease, breast cancer, depression, heart disease, epilepsy), elucidating advanced endeavors in their diagnosis and treatment through the lens of artificial intelligence. Our survey not only delineates detailed diagnostic methodologies across varying modalities but also underscores commonly utilized public datasets, the intricacies of feature engineering, prevalent classification models, and envisaged challenges for future endeavors. In essence, our research endeavors to contribute to the advancement of diagnostic methodologies, furnishing invaluable insights for clinical decision making.

Identification and effective regulation of scarb1 gene involved in pigmentation change in autotetraploid Carassius auratus.

The autotetraploid Carassius auratus (4nRR, 4 n=200, RRRR) is derived from whole-genome duplication of Carassius auratus red var. (RCC, 2 n=100, RR). In the current study, we demonstrated that chromatophores and pigment changes directly caused the coloration and variation of 4nRR skin (red in RCC, brownish-yellow in 4nRR). To further explore the molecular mechanisms underlying coloration formation and variation in 4nRR, we performed transcriptome profiling and molecular functional verification in RCC and 4nRR. Results revealed that scarb1, associated with carotenoid metabolism, underwent significant down-regulation in 4nRR. Efficient editing of this candidate pigment gene provided clear evidence of its significant role in RCC coloration. Subsequently, we identified four divergent scarb1 homeologs in 4nRR: two original scarb1 homeologs from RCC and two duplicated ones. Notably, three of these homeologs possessed two highly conserved alleles, exhibiting biased and allele-specific expression in the skin. Remarkably, after precise editing of both the original and duplicated scarb1 homeologs and/or alleles, 4nRR individuals, whether singly or multiply mutated, displayed a transition from brownish-yellow skin to a cyan-gray phenotype. Concurrently, the proportional areas of the cyan-gray regions displayed a gene-dose correlation. These findings illustrate the subfunctionalization of duplicated scarb1, with all scarb1 genes synergistically and equally contributing to the pigmentation of 4nRR. This is the first report concerning the functional differentiation of duplicated homeologs in an autopolyploid fish, substantially enriching our understanding of coloration formation and change within this group of organisms.

Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer associated with a poor prognosis. Effective targeted therapy alone or in combination for treating advanced CRC remains to be a major clinical challenge. Here, we propose the therapeutic efficacy and molecular mechanism underlying RC48, a FDA-approved anti-HER2 antibody conjugate via a cleavable linker to the microtubule inhibitor monomethyl auristatin E (MMAE), either alone or in combination with gemcitabine (GEM) in various models of HER2-positive advanced CRC. Our findings demonstrated that HER2 was widely expressed and located on the plasma membrane of CRC patient specimens, PDX xenograft tumors and cell lines. It confirmed that RC48 alone significantly targeted and eradicated HER2 positive CRC tumor in these models. Moreover, we screened a panel of FDA-approved first-line chemotherapy drugs in vitro. We found that GEM exhibited stronger antiproliferative activity compared to the other first-line anti-cancer agents. Furthermore, combination therapy of RC48 and GEM significantly showed synergetic antitumor activity in vitro and in vivo. To gain further mechanistic insights into the combination therapy, we performed RNA-seq analysis. The results revealed that combination treatment of RC48 and GEM regulated multiple signaling pathways, such as PI3K-AKT, MAPK, p53, Foxo, apoptosis, cell cycle and cell senescence, etc., to exert its antitumor activity in CRC cells. Collectively, these preclinical findings demonstrated that RC48 alone or combinational therapy exerted promising antitumor activity, and meriting the preclinical framework for combinational therapy of anti-HER2 drug conjugate drug and chemotherapy drugs for HER2-positive patients with advanced CRC.