Acute lung injury: a view from the perspective of necroptosis.

BACKGROUND: ALI/ARDS is a syndrome of acute onset characterized by progressive hypoxemia and noncardiogenic pulmonary edema as the primary clinical manifestations. Necroptosis is a form of programmed cell necrosis that is precisely regulated by molecular signals. This process is characterized by organelle swelling and membrane rupture, is highly immunogenic, involves extensive crosstalk with various cellular stress mechanisms, and is significantly implicated in the onset and progression of ALI/ARDS. METHODS: The current body of literature on necroptosis and ALI/ARDS was thoroughly reviewed. Initially, an overview of the molecular mechanism of necroptosis was provided, followed by an examination of its interactions with apoptosis, pyroptosis, autophagy, ferroptosis, PANOptosis, and NETosis. Subsequently, the involvement of necroptosis in various stages of ALI/ARDS progression was delineated. Lastly, drugs targeting necroptosis, biomarkers, and current obstacles were presented. CONCLUSION: Necroptosis plays an important role in the progression of ALI/ARDS. However, since ALI/ARDS is a clinical syndrome caused by a variety of mechanisms, we emphasize that while focusing on necroptosis, it may be more beneficial to treat ALI/ARDS by collaborating with other mechanisms.

Association of Serum Uric Acid with Non-Valvular Atrial Fibrillation: A Retrospective Study in China.

Purpose: The association between serum uric acid (SUA) and atrial fibrillation (AF) has been widely focused on and studied in recent years. However, the exact association between SUA and AF is unclear, and the effect of gender on the association between SUA levels and AF has been controversial. This study aimed to investigate the association between SUA levels and non-valvular AF (NVAF) and the potential effect of gender on it. Patients and Methods: A total of 866 NVAF patients (463 males, age 69.44 ± 8.07 years) and 646 sex-matched control patients in sinus rhythm, with no history of arrhythmia were included in this study. t-test, ANOVA, and chi-square test were used for baseline data analysis. The receiver operating characteristic curve, logistic regression and Pearson correlation analysis were used for correlation analysis. Results: Compared to controls, NVAF patients exhibited higher SUA (P<0.001). After adjusting for confounders of NVAF, SUA remained significantly associated with NVAF, regardless of gender (OR= 1.31, 95% CI 1.18-1.43, P<0.001). SUA demonstrated higher predictability and sensitivity in predicting the occurrence of female NVAF compared to male (area under the curve was 0.68 (95% CI 0.64-0.72, P<0.001), sensitivity 87.3%), with the optimal cut-off point identified as 5.72 mg/dL. Furthermore, SUA levels correlated with APOA1, Scr and NT-proBNP in NVAF patients. SUA levels varied significantly among NVAF subtypes. Conclusion: High SUA levels were independently associated with NVAF, regardless of gender. SUA exhibited higher predictability and sensitivity in predicting the occurrence of NVAF in females compared to males. High SUA levels may affect other NVAF-related factors and participate in the pathophysiological process of NVAF.

Magnetically powered microwheel thrombolysis of occlusive thrombi in zebrafish.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for ischemic stroke but carries significant risks, including major hemorrhage. Additional options are needed, especially in small vessel thrombi which account for ~25% of ischemic strokes. We have previously shown that tPA-functionalized colloidal microparticles can be assembled into microwheels (µwheels) and manipulated under the control of applied magnetic fields to enable rapid thrombolysis of fibrin gels in microfluidic models of thrombosis. Transparent zebrafish larvae have a highly conserved coagulation cascade that enables studies of hemostasis and thrombosis in the context of intact vasculature, clotting factors, and blood cells. Here, we show that tPA-functionalized µwheels can perform rapid and targeted recanalization in vivo. This effect requires both tPA and µwheels, as minimal to no recanalization is achieved with tPA alone, µwheels alone, or tPA-functionalized microparticles in the absence of a magnetic field. We evaluated tPA-functionalized µwheels in CRISPR-generated plasminogen (plg) heterozygous and homozygous mutants and confirmed that tPA-functionalized µwheels are dose-dependent on plasminogen for lysis. We have found that magnetically powered µwheels as a targeted tPA delivery system are dramatically more efficient at plasmin-mediated thrombolysis than systemic delivery in vivo. Further development of this system in fish and mammalian models could enable a less invasive strategy for alleviating ischemia that is safer than directed thrombectomy or systemic infusion of tPA.

Generation of superposed orbital angular momentum beams using a free-electron laser oscillator.

With wavelength tunability, free-electron lasers (FELs) are well-suited for generating orbital angular momentum (OAM) beams in a wide photon energy range. We report here the first experimental demonstration of OAM beam generation using an oscillator FEL with the tens of picosecond pulse duration. Lasing around 458 nm, we have produced the four lowest orders of superposed Laguerre-Gaussian beams using a very long FEL resonator of 53.73 m. The produced beams have good beam quality, excellent stability, and substantial average power. We have also developed a pulsed operation mode for these beams with a highly reproducible temporal structure for a range of repetition rate of 1-30 Hz. This development can be extended to short wavelengths, for example to x-rays using a future x-ray FEL oscillator. The OAM operation of such a storage-ring FEL also paves the way for the generation of OAM gamma-ray beams via inverse Compton scattering.

Model averaging estimation of panel data models with many instruments and boosting.

Applied researchers often confront two issues when using the fixed effect-two-stage least squares (FE-2SLS) estimator for panel data models. One is that it may lose its consistency due to too many instruments. The other is that the gain of using FE-2SLS may not exceed its loss when the endogeneity is weak. In this paper, an L2Boosting regularization procedure for panel data models is proposed to tackle the many instruments issue. We then construct a Stein-like model-averaging estimator to take advantage of FE and FE-2SLS-Boosting estimators. Finite sample properties are examined in Monte Carlo and an empirical application is presented.

A compact multi-pixel superconducting nanowire single-photon detector array supporting gigabit space-to-ground communications.

Classical and quantum space-to-ground communications necessitate highly sensitive receivers capable of extracting information from modulated photons to extend the communication distance from near-earth orbits to deep space explorations. To achieve gigabit data rates while mitigating strong background noise photons and beam drift in a highly attenuated free-space channel, a comprehensive design of a multi-functional detector is indispensable. In this study, we present an innovative compact multi-pixel superconducting nanowire single-photon detector array that integrates near-unity detection efficiency (91.6%), high photon counting rate (1.61 Gcps), large dynamic range for resolving different photon numbers (1-24), and four-quadrant position sensing function all within one device. Furthermore, we have constructed a communication testbed to validate the advantages offered by such an architecture. Through 8-PPM (pulse position modulation) format communication experiments, we have achieved an impressive maximum data rate of 1.5 Gbps, demonstrating sensitivities surpassing previous benchmarks at respective speeds. By incorporating photon number information into error correction codes, the receiver can tolerate maximum background noise levels equivalent to 0.8 photons/slot at a data rate of 120 Mbps-showcasing a great potential for daylight operation scenarios. Additionally, preliminary beam tracking tests were conducted through open-loop scanning techniques, which revealed clear quantitative dependence indicating sensitivity variations based on beam location. Based on the device characterizations and communication results, we anticipate that this device architecture, along with its corresponding signal processing and coding techniques, will be applicable in future space-to-ground communication tasks.

Optogenetic Activation of Peripheral Somatosensory Neurons in Transgenic Mice as a Neuropathic Pain Model for Assessing the Therapeutic Efficacy of Analgesics.

Optogenetics is a novel biotechnology widely used to precisely manipulate a specific peripheral sensory neuron or neural circuit. However, the use of optogenetics to assess the therapeutic efficacy of analgesics is elusive. In this study, we generated a transgenic mouse stain in which all primary somatosensory neurons can be optogenetically activated to mimic neuronal hyperactivation in the neuropathic pain state for the assessment of analgesic effects of drugs. A transgenic mouse was generated using the advillin-Cre line mated with the Ai32 strain, in which channelrhodopsin-2 fused to enhanced yellow fluorescence protein (ChR2-EYFP) was conditionally expressed in all types of primary somatosensory neurons (advillincre/ChR2+/+). Immunofluorescence and transdermal photostimulation on the hindpaws were used to verify the transgenic mice. Optical stimulation to evoke pain-like paw withdrawal latency was used to assess the analgesic effects of a series of drugs. Injury- and pain-related molecular biomarkers were investigated with immunohistofluorescence. We found that the expression of ChR2-EYFP was observed in many primary afferents of paw skin and sciatic nerves and in primary sensory neurons and laminae I and II of the spinal dorsal horns in advillincre/ChR2+/+ mice. Transdermal blue light stimulation of the transgenic mouse hindpaw evoked nocifensive paw withdrawal behavior. Treatment with gabapentin, some channel blockers, and local anesthetics, but not opioids or COX-1/2 inhibitors, prolonged the paw withdrawal latency in the transgenic mice. The analgesic effect of gabapentin was also verified by the decreased expression of injury- and pain-related molecular biomarkers. These optogenetic mice provide a promising model for assessing the therapeutic efficacy of analgesics in neuropathic pain.

A multi-parameter intrahepatic cholangiocarcinoma scoring system based on modified contrast-enhanced ultrasound LI-RADS M criteria for differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma.

PURPOSE: To develop a multi-parameter intrahepatic cholangiocarcinoma (ICC) scoring system and compare its diagnostic performance with contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system M (LR-M) criteria for differentiating ICC from hepatocellular carcinoma (HCC). METHODS: This retrospective study enrolled 62 high-risk patients with ICCs and 62 high-risk patients with matched HCCs between January 2022 and December 2022 from two institutions. The CEUS LR-M criteria was modified by adjusting the early wash-out onset (within 45 s) and the marked wash-out (within 3 min). Then, a multi-parameter ICC scoring system was established based on clinical features, B-mode ultrasound features, and modified LR-M criteria. RESULT: We found that elevated CA 19-9 (OR=12.647), lesion boundary (OR=11.601), peripheral rim-like arterial phase hyperenhancement (OR=23.654), early wash-out onset (OR=7.211), and marked wash-out (OR=19.605) were positive predictors of ICC, whereas elevated alpha-fetoprotein (OR=0.078) was a negative predictor. Based on these findings, an ICC scoring system was established. Compared with the modified LR-M and LR-M criteria, the ICC scoring system showed the highest area under the curve (0.911 vs. 0.831 and 0.750, both p<0.05) and specificity (0.935 vs. 0.774 and 0.565, both p<0.05). Moreover, the numbers of HCCs categorized as LR-M decreased from 27 (43.5%) to 14 (22.6%) and 4 (6.5%) using the modified LR-M criteria and ICC scoring system, respectively. CONCLUSION: The modified LR-M criteria-based multi-parameter ICC scoring system had the highest specificity for diagnosing ICC and reduced the number of HCC cases diagnosed as LR-M category.

Protective effects of chlorogenic acid against cyclophosphamide induced liver injury in mice.

We investigated possible protective effects of chlorogenic acid (CGA) against cyclophosphamide (CP) induced hepatic injury in mice. We measured aminotransferase alanine transaminase (ALT) and aspartate transaminase (AST) levels in the serum. We assayed catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in hepatic tissue. We assessed expression of nuclear transcription factor 2 (Nrf2) and Kelch sample related protein-1 (keap1) proteins in hepatic tissues using immunohistochemistry. The relative mRNA expression levels of heme oxygenase-1 (HO-1), NADH quinone oxidoreductase 1 (NQO1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Hematoxylin & eosin staining was used to assess liver histopathology. We found that administration of CGA prior to induction of injury by CP decreased serum ALT, AST and MDA expressions in hepatic tissue, while CAT, SOD, GSH and GSH-Px concentrations were increased. We found that hepatocytes of animals administered CGA gradually returned to normal morphology. CGA increased the protein expression of Nrf2 in murine hepatic tissue. Administration of CGA up-regulated mRNA expression levels of HO-1, NQO1, TNF-α and IL-6 in hepatic tissue. CGA exhibited a marked protective effect on CP induced liver injury in mice.

Quantitative analysis of pre-treatment dynamic contrast-enhanced ultrasound for assessing the response of colorectal liver metastases to chemotherapy plus targeted therapy: a dual-institutional study.

OBJECTIVES: To investigate the clinical value of pre-treatment quantitative contrast-enhanced ultrasound (CEUS) in assessing the response of colorectal liver metastases (CRLM) to chemotherapy plus targeted therapy. METHODS: This study retrospectively enrolled 50 CRLM patients from the Zhongshan Hospital, Fudan University as the training cohort and 14 patients from Shanghai Tenth People's Hospital as the testing cohort. Patients underwent the CEUS examination before receiving chemotherapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI) plus targeted therapy (Bevacizumab or Cetuximab). The therapy response was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 based on pre-treatment CT and 3-month follow-up CT after therapy. Dynamic analysis was performed by VueBox® software. Time-intensity curves with quantitative perfusion parameters were obtained. In the training cohort, univariable and multivariable logistic regression analyses were used to develop the predictive model of therapy response. The predictive performance of the developed model was validated in the testing cohort. RESULTS: After the logistic regression analyses, the peak enhancement (PE) (odds ratio = 1.640; 95% confidence intervals [CI] 1.022-2.633) and time to peak (TTP) (odds ratio = 0.495; 95% CI 0.246-0.996) were determined as independent predictive factors. PE and TTP generated from VueBox® were not affected by ultrasound instruments and contrast agent dosage in therapy response evaluation (P > 0.05). The logistic regression model achieved satisfactory prediction performance (area under the curve: 0.923 in the training cohort and 0.854 in the testing cohort). CONCLUSION: CEUS with dynamic quantitative perfusion analysis, which presents high consistency, has potential practical value in predicting the response of CRLM to chemotherapy plus targeted therapy.

Response Evaluation Using Contrast-Enhanced Ultrasound for Unresectable Advanced Hepatocellular Carcinoma Treated With Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy.

OBJECTIVE: The aim of the work described here was to evaluate the role of contrast-enhanced ultrasound (CEUS) in response evaluation for unresectable advanced hepatocellular carcinoma (HCC) treated with tyrosine kinase inhibitors (TKIs) plus anti-programmed cell death protein-1 (PD-1) antibody therapy. METHODS: A prospective cohort of consecutive patients with HCC who received combined TKI/anti-PD-1 antibody treatment for unresectable HCC between January 2022 and October 2022 was included in this study. The patients underwent unenhanced ultrasound (US) and CEUS examinations before treatment and at follow-up. Changes in the largest diameters of the target tumor on unenhanced US and the largest diameters of the enhancing target tumors on CEUS were evaluated. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with unenhanced US and magnetic resonance imaging/computed tomography (MRI/CT) and modified RECIST (mRECIST) with CEUS and CEMRI/CT were used to assess treatment response. RESULTS: A total of 24 HCC patients (23 men and 1 woman; mean age: 56.5 ± 8.5 y; Barcelona Clinic Liver Cancer stage C, 62.5%; 29 intrahepatic target tumors) were studied. Calculations of degree of necrosis in the target tumors revealed no significant differences between CEUS and CEMRI/CT (44.5 ± 36.2% vs. 45.3 ± 36.8%, p = 0.862). As for the differentiation of responders from non-responders, the agreement between RECIST version 1.1 of unenhanced US and mRECIST-CEUS was poor (κ coefficient = 0.233). Meanwhile, there was a high degree of concordance between mRECIST-CEUS and mRECIST-CEMRI/CT (κ coefficient = 0.812). CONCLUSION: CEUS proved to be superior to baseline US and is comparable to CEMRI/CT in defining treatment outcome for combined TKI/anti-PD-1 antibody therapy.

Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.

Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.

PRP significantly promotes the adhesion and migration of vascular smooth muscle cells on stent material.

BACKGROUND: The adhesion and survival state of cells on scaffold material is a major problem in tissue-engineered blood vessel (TEBV) culture. Platelet-rich plasma (PRP) contains a large amount of biologically active factors and fibrin, which is expected to play an important role in TEBV culture. PURPOSE: To combine PRP with cells and scaffold material to promote cell adhesion and biological activity on the scaffold material. METHODS: The adhesion status and migration of SMCs under the optimal concentration suitable for SMC growth and the optimal concentration of PRP were examined by scanning electron microscopy, HE staining, CCK-8 assays, qPCR, WB, and other experimental methods and compared with those under the conventional culture (20% FBS); finally, the effect of PRP on the deposition of ECM in vascular tissue engineering culture was verified by three-dimensional culture. RESULTS: PRP at 20% is a suitable concentration for SMCs. Compared with the control group, the 20% PRP group had better migration, and the number of SMC adhesions was significantly higher than that of the control group. In addition, collagen deposition in the experimental group was significantly higher than that in the control group. CONCLUSION: PRP (20%) can promote SMC adhesion, migration, and collagen deposition on the scaffold material.

Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

Research progress on the activation mechanism of NLRP3 inflammasome in septic cardiomyopathy.

Sepsis is an uncontrolled host response to infection, resulting in a clinical syndrome involving multiple organ dysfunctions. Cardiac damage is the most common organ damage in sepsis. Uncontrolled inflammatory response is an important mechanism in the pathogenesis of septic cardiomyopathy (SCM). NLRP3 inflammasome promotes inflammatory response by controlling the activation of caspase-1 and the release of pro-inflammatory cytokines interleukin IL-1ß and IL-18. The role of NLRP3 inflammasome has received increasing attention, but its activation mechanism and regulation of inflammation in SCM remain to be investigated.

Protein Labeling Facilitates the Understanding of Protein Corona Formation via Fluorescence Resonance Energy Transfer and Fluorescence Correlation Spectroscopy.

Once nanoparticles enter into the biological milieu, nanoparticle-biomacromolecule complexes, especially the protein corona, swiftly form, which cause obvious effects on the physicochemical properties of both nanoparticles and proteins. Here, the thermodynamic parameters of the interactions between water-soluble GSH-CdSe/ZnS core/shell quantum dots (GSH-QDs) and human serum albumin (HSA) were investigated with the aid of labeling fluorescence of HSA. It was proved that the labeling fluorescence originating from a fluorophore (BDP-CN for instance) could be used to investigate the interactions between QDs and HSA. Gel electrophoresis displayed that the binding ratio between HSA and QDs was ∼2:1 by direct visualization. Fluorescence resonance energy transfer (FRET) results indicated that the distance between the QDs and the fluorophore BDP-CN in HSA was 7.2 nm, which indicated that the distance from the fluorophore to the surface of the QDs was ∼4.8 nm. Fluorescence correlation spectroscopy (FCS) results showed that HSA formed a monolayer of a protein corona with a thickness of 5.5 nm. According to the spatial structure of HSA, we could speculate that the binding site of QDs was located at the side edge (not the triangular plane) of HSA with an equilateral triangular prism. The elaboration of the thermodynamic parameters, binding ratio, and interaction orientation will highly improve the fundamental understanding of the formation of protein corona. This work has guiding significance for the exploration of the interactions between proteins and nanomaterials.

Tandem Mass Tag-Based Proteomic Profiling Identifies Biomarkers in Drainage Fluid for Early Detection of Anastomotic Leakage after Rectal Cancer Resection.

Anastomotic leakage (AL), one of the most severe complications in rectal surgery, is often diagnosed late because of the low specificity of the clinical symptoms and limitations of current clinical investigations. Identification of patients with early AL remains challenging. Here, we explored the protein expression profiles of AL patients to provide potential biomarkers to identify AL in patients who undergo surgery for rectal cancer. We screened differentially expressed proteins (DEPs) in drainage fluid from AL and non-AL patients using a tandem mass tag method. A total of 248 DEPs, including 98 upregulated and 150 downregulated proteins, were identified between AL and non-AL groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that DEPs were enriched in neutrophil degranulation, bacterial infection, proteolysis, hemostasis, and complement and coagulation cascades. The results of enzyme-linked immunosorbent assay validated that the expression of the top three upregulated DEPs, AMY2A, RETN, and CELA3A, was significantly increased in the drainage fluid of AL patients, compared with that of non-AL patients (AMY2A, P = 0.001; RETN, P < 0.0001; and CELA3A, P = 0.023). Thus, our findings provide several potential biomarkers for the early diagnosis of AL after rectal cancer resection.

Magnetically Powered Microwheel Thrombolysis of Occlusive Thrombi in Zebrafish.

Tissue plasminogen activator (tPA) is the only FDA approved treatment for ischemic stroke but carries significant risks, including major hemorrhage. Additional options are needed, especially in small vessel thrombi which account for ~25% of ischemic strokes. We have previously shown that tPA-functionalized colloidal microparticles can be assembled into microwheels (µwheels) and manipulated under the control of applied magnetic fields to enable rapid thrombolysis of fibrin gels in microfluidic models of thrombosis. Providing a living microfluidic analog, transparent zebrafish larvae have a highly conserved coagulation cascade that enables studies of hemostasis and thrombosis in the context of intact vasculature, clotting factors, and blood cells. Here we show that tPA-functionalized µwheels can perform rapid and targeted recanalization in vivo. This effect requires both tPA and µwheels, as minimal to no recanalization is achieved with tPA alone, µwheels alone, or tPA-functionalized microparticles in the absence of a magnetic field. We evaluated tPA-µwheels in CRISPR-generated plasminogen (plg) heterozygous and homozygous mutants and confirmed that tPA-µwheels are dose-dependent on plasminogen for lysis. We have found that magnetically powered µwheels as a targeted tPA delivery system are dramatically more efficient at plasmin-mediated thrombolysis than systemic delivery in vivo. Further development of this system in fish and mammalian models could enable a less invasive strategy for alleviating ischemia that is safer than directed thrombectomy or systemic infusion of tPA.

Efficacy and safety of metformin in combination with chemotherapy in cancer patients without diabetes: systematic review and meta-analysis.

Background: The results of a meta-analysis of retrospective studies suggest that the use of metformin in cancer patients may prolong progression-free disease survival and overall survival. However, the studies included in the meta-analysis did not strictly distinguish between patients with or without type 2 diabetes mellitus. Therefore, further studies are needed to assess whether the use of adjuvant chemotherapy with metformin in cancer patients without diabetes improves prognosis. Method: Systematic searches of Embase, Pubmed, and The Cochrane library were performed for the subject terms metformin and neoplasm and for free words. Data related to PFS, OS were extracted according to inclusion exclusion criteria. The data were combined and meta-analysis was performed using Review Manager 5.4 to confirm the efficacy and safety of metformin administration. Results: There were 3228 publications retrieved from the database and a total of 13 publications with 955 patients were included in the meta-analysis after screening. All included studies were randomised controlled trials. Metformin combined with adjuvant chemotherapy did not improve progression-free survival (HR=1,95CI 0.79-1.25), overall survival (HR=0.91,95% CI 0.69-1.20) and did not improve objective disease response rates in patients. There was no significant difference in grade 3-4 adverse reactions compared to placebo. Conclusion: In this meta-analysis of randomised controlled trial studies, we found that chemotherapy in combination with metformin in cancer patients without diabetes did not prolong progression-free survival and overall survival and improved disease control in patients, although there was no significant difference in terms of safety. More high-quality randomised controlled trials are needed in the future to confirm the in vivo anti-tumour activity and survival benefit of metformin.

Spatiotemporal and kinematic gait analysis in patients with knee osteoarthritis and femoral varus deformity.

BACKGROUND: Knee osteoarthritis (OA) is commonly combined with the presentation of a coronal deformity of the knee. The bony origin of the knee varus deformity can be classified as tibial origin, femoral origin, or a combination of tibial and femoral causes. Deformities of tibial origin are mostly common clinically, while patients with knee OA with femoral varus deformity are less common. RESEARCH QUESTION: Do hip, knee and ankle kinematics and spatiotemporal parameters differ between patients with knee OA with femoral varus deformity and healthy subjects? METHODS: Twenty-five patients (14 females and 11 males) with knee OA and femoral varus deformity and 20 healthy subjects (12 males and 8 females) as control group were included in this study. The kinematic parameters of the hip-knee-ankle joint and spatiotemporal gait parameters were included in the study. RESULTS: This study found that the step speed and step length of the knee OA with femoral varus (KOAF) group were smaller than those of the control group, while double support period percentage was greater in the KOAF group. Significant differences were found in the maximum knee extension angle, maximum knee flexion angle, knee flexion range of motion, maximum hip flexion angle, maximum hip extension angle, and hip flexion range of motion between the two groups. After comparing the ankle motion between the two groups, significant differences were found in the maximum eversion angle, inversion range of motion, maximum ankle abduction angle, and abduction range of motion. SIGNIFICANCE: Knee OA with femoral varus deformity causes adaptive changes in the kinematic parameters of hip, knee and ankle joints and spatiotemporal gait parameters to alleviate symptoms and maintain normal activity.