Tim-3 facilitates immune escape in benzene-induced acute myeloid leukemia mouse model by promoting macrophage M2 polarization.

Benzene poisoning can cause acute myeloid leukemia (AML) through a variety of passways. Tim-3 has gained prominence as a potential candidate in mediating immunosuppression in tumor microenvironments. The macrophage polarization is also related to immune escape. Herein, we reported that Tim-3 and macrophage M2 polarization play a vital role in benzene-induced AML. First, the benzene-induced AML C3H/He mouse model was constructed by subcutaneously injecting 250 mg/kg of benzene. After six months, macrophage phenotype, cytokines, and Tim-3 expression levels were investigated. Flow cytometry assay revealed that the T-cell inhibitory receptor Tim-3 was significantly upregulated in both bone marrow and spleen of the benzene-induced AML mouse model. Elisa's results displayed a decreased serum level of IL-12 while increased TGF-ß1. Mechanistically, changes in cytokine secretion promote the growth of M2-type macrophages in the bone marrow and spleen, as determined by immunofluorescence assay. The increased levels of PI3K, AKT, and mTOR in the benzene-exposure group further proved the crucial role of Tim-3 in regulating the functional status of macrophages in the AML microenvironment. These results demonstrate that Tim-3 and macrophage polarization may play a vital role during the immune escape of the benzene-induced AML. This study provides a new potential intervention site for immune checkpoint-based AML therapeutic strategy.

Analysis of Microbial Diversity in South Shetland Islands and Antarctic Peninsula Soils Based on Illumina High-Throughput Sequencing and Cultivation-Dependent Techniques.

To assess the diversity of bacterial taxa in Antarctic soils and obtain novel microbial resources, 15 samples from 3 sampling sites (DIS5, GWS7, FPS10) of South Shetland Islands and 2 sampling sites (APS18, CIS17) of Antarctic Peninsula were collected. High-throughput sequencing (HTS) of 16S rRNA genes within these samples was conducted on an Illumina Miseq platform. A total of 140,303 16S rRNA gene reads comprising 802 operational taxonomic units (OTUs) were obtained. After taxonomic classification, 25 phyla, 196 genera, and a high proportion of unidentified taxa were detected, among which seven phyla and 99 genera were firstly detected in Antarctica. The bacterial communities were dominated by Actinomycetota (40.40%), Pseudomonadota (17.14%), Bacteroidota (10.55%) and Chloroflexota (10.26%). Based on the HTS analyses, cultivation-dependent techniques were optimized to identify the cultivable members. A total of 30 different genera including 91 strains were obtained, the majority of which has previously been reported from Antarctica. However, for the genera Microterricola, Dyadobacter, Filibacter, Duganella, Ensifer, Antarcticirhabdus and Microvirga, this is the first report in Antarctica. In addition, seven strains represented novel taxa, two of which were psychropoilic and could be valuable resources for further research of cold-adaptability and their ecological significance in Antarctica.

Study on the therapeutic effect of glucocorticoids on acute kidney injury in rats exposed to diquat.

AIMS: To preliminarily explore, whether glucocorticoids have a therapeutic effect on diquat-induced acute kidney injury in rats. METHOD: 150 Wistar rats were randomly divided into six groups: exposure model group (DQ group), dexamethasone control group (GC group), blank control group (Ctrl group), dexamethasone 2.1 mg/kg dose group (DQ+L-GC group), dexamethasone 4.2 mg/kg dose group (DQ+M-GC group), and dexamethasone 8.4 mg/kg dose group (DQ+H-GC group), with 25 rats in each group. Each group was further divided into five subgroups, 24 h, 3 d, 7 d, 14 d, and 21 d after exposure, according to the feeding time and the course of treatment, with five animals in each subgroup. The rats in DQ, DQ+L-GC, DQ+M-GC, and DQ+H-GC groups were administered 115.5 mg/kg diquat by gavage, respectively. Moreover, 30 min after gavage, rats in DQ+L-GC group, DQ+M-GC group, DQ+H-GC group and GC group were intragastric administered dexamethasone 2.1 mg/kg, 4.2 mg/kg, 8.4 mg/kg and 8.4 mg/kg, respectively. After 7 days, the intraperitoneal injection of dexamethasone was changed to 6.3 mg/kg prednisone by intragastric administration. Subsequently, 7 days later, it was changed to 3.15 mg/kg prednisone by intragastric administration until the end of the experiment on 21 days. After the start of the experiment, changes in the conditions of the rats in each group were observed at a fixed time every day, changes in the body weight of the rats were monitored at the same time, and the death of the rats was recorded at 24 h, 3 d, 7 d, 14 d, and 21 d after exposure. The rats were sacrificed by an intraperitoneal injection of 100 mg/kg sodium pentobarbital overdose. Blood was collected by puncture of the inferior vena cava, used to determine Cr and BUN. The upper segment of the left kidney was collected for histopathological examination. Elisa was used to detect neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in the lower segment of left kidney. TLR4, Myd88, and NF-κB were detected in the right kidney. RESULTS: (1) After exposure, most rats in DQ group, DQ+L-GC group, DQ+M-GC group and DQ+H-GC group showed shortness of breath, oliguria, diarrhea, yellow hair and other symptoms. No symptoms and related signs were observed in Ctrl group and GC group. (2) The weight of rats in the Ctrl group and the GC group increased slowly during the test. the body weight of the rats in the DQ, DQ+L-GC, DQ+M-GC, and DQ+H-GC groups continued to decrease after self-infection. Body weight dropped to the lowest point at approximately 7 d, and gradually increased from 7 d to 21 d. (3) A small amount of capillary congestion in the medulla was observed after 7 days in the GC group. The DQ group showed tubular atrophy, edema of the epithelial cells, and over time, the tubules were seen dilated and became irregular in shape; large amount of capillary congestion was also observed in the renal cortex and medulla. The renal injury in the DQ+L-GC group was less than that in the DQ group. DQ+H-GC group had no obvious injury before 7 d, but more renal tubules were seen in the DQ+H-GC group from 7 d to 14 d. (4) Compared with the DQ group, there was no difference before 14 d, and at 14 d-21 d, DQ+L-GC group, DQ+M-GC group, DQ+H-GC group all had different degrees of decline. NGAL content: Compared with the DQ group, the content of NGAL and KIM-1 in kidney tissue of the DQ+L-GC, DQ+M-GC, and DQ+H-GC groups decreased compared with the DQ group at each time node. (5) Compared with the Ctrl group, the expression of TNF-α, TLR4, MyD88, NF-κB in the DQ, DQ+L-GC, DQ+M-GC, and DQ+H-GC groups at each time node increased in the renal tissue. The content of TNF-α, TLR4, MyD88, NF-κB in kidney tissue of the DQ+L-GC, DQ+M-GC, and DQ+H-GC groups at each time node was lower than that in the DQ group. CONCLUSION: (1) Diquat can cause kidney damage in rats, mainly manifested as renal tubular atrophy, epithelial cell edema, capillary congestion and dilation, and the renal function damage indicators have been improved to varying degrees. (2) Glucocorticoids have therapeutic effects on acute kidney injury in rats exposed to diquat. During the treatment, the efficacy of glucocorticoids did not increase with increasing doses after reaching a dose of 4.2 mg/kg. (3) TLR4 receptor-mediated TLR4/Myd88/NF-κB signaling pathway is involved in the inflammatory response of acute kidney injury in diquat poisoning rats. Glucocorticoids can inhibit the inflammatory response, thereby affecting the expression of TLR4/Myd88/NF-κB signaling pathway-related proteins.

Diagnosis and treatment of acquired factor VIII deficiency: a case report and literature review.

Acquired haemophilia A (AHA) is a rare haemorrhagic disease characterized by spontaneous extensive subcutaneous haemorrhage and soft tissue haematoma. The activated partial thromboplastin time is significantly prolonged and cannot be corrected by normal plasma. Approximately 50% of AHA patients lack a specific aetiology, so this can easily result in a misdiagnosis. This current case report describes a 27-year-old male that presented with gingival bleeding, haematuria and haematochezia with no obvious cause. At first, it was thought that he might have experienced anticoagulant rodenticide poisoning, but the subsequent anticoagulant rodenticide test was negative. At the same time, the patient was screened for mutations associated with bleeding and coagulation diseases. Two mutations were identified: a p.Y471H mutation the plasminogen activator, tissue type (PLAT) gene; and a p.Y244Y mutation the serpin family E member 1 (SERPINE1) gene. It should be noted that patient had no previous history of thrombosis or haemorrhagic disease, which confused the diagnosis. A professional haemophilia research centre provided clarification of the diagnosis when anti-factor VIII antibodies were detected. The patient was treated with 30 mg/day prednisone orally. Multiple follow-up examinations showed continuous complete remission. No factor VIII antibodies were detected in his blood and coagulation factor VIII increased significantly.

Clinical Analysis of Acute Organophosphorus Pesticide Poisoning and Successful Cardiopulmonary Resuscitation: A Case Series.

Acute organophosphorus pesticide poisoning (AOPP) with cardiac arrest has an extremely high mortality rate, and corresponding therapeutic strategies have rarely been reported. Therefore, this study aimed to explore the prognostic factors and effective treatments of AOPP-related cardiac arrest. This retrospective study was conducted in our department in the years 2018-2021. We conducted a descriptive analysis of the clinical manifestations, rescue strategies, and prognosis of patients with AOPP who had experienced cardiac arrest and successful cardiopulmonary resuscitation. This study included six cases of patients with AOPP in addition to cardiac arrest; in four cases, cardiac arrest occurred <12 h after ingestion, and in two, cardiac arrest occurred more than 48 h after ingestion. Five patients had not undergone hemoperfusion therapy before cardiac arrest, and all six were treated with atropine during cardiopulmonary resuscitation and subsequent pralidoxine. Four patients recovered and were discharged from the hospital, one died in our department, and one was transferred to a local hospital and died there 2 h later. The last two patients had severe pancreatic injuries and disseminated intravascular coagulation. This, along with their death, might have been related to their prognosis. Cardiac arrest can occur in patients with severe AOPP for whom antidote administration was insufficient or not timely. Application of atropine and pralidoxine in a timely manner after cardiac arrest following AOPP is the key to successful treatment. This study provides useful guidelines for the treatment of similar cases in the future.

Two cases of methaemoglobinaemia and haemolysis due to poisoning after skin absorption of 4-chloro-1-nitrobenzene.

INTRODUCTION: While 4-chloro-1-nitrobenzene has oxidising properties and can lead to methaemoglobinaemia and haemolysis, such reports are rare. We herein describe two cases of 4-chloro-1-nitrobenzene poisoning after skin exposure and detail relevant clinical characteristics and treatment outcomes. CASE PRESENTATION: A 45-year-old man and his 32-year-old male co-worker presented at our department shortly after skin exposure to 4-chloro-1-nitrobenzene. They developed similar symptoms, including dizziness, dyspnoea, excessive fatigue, and coma. Patients' chest inspection yielded normal findings. Despite maximal oxygen supplementation, neither patient exhibited improvements in the following clinical parameters: diffuse cyanosis, chocolate-coloured blood, and decreased pulse oximetry. For patients 1 and 2, methaemoglobin levels at admission were 78.6% and 63.6%, and 4-chloro-1-nitrobenzene concentrations were 4.12 µg/mL and 2.89 µg/mL, respectively. Their symptoms and methaemoglobin levels improved after we cautiously administered methylene blue; we subsequently detected oxidative haemolysis (confirmed by peripheral blood smears) that later resolved without further aggravation. No further episodes of anaemia were documented via telephone follow-up for eight months after hospital discharge for either patient. DISCUSSION: Typical features of methaemoglobinaemia included diffuse cyanosis, dark chocolate-coloured blood, elevated partial pressure of oxygen, and decreased pulse oximetry saturation. Haemolysis likely occurred secondary to the toxic effects of 4-chloro-1-nitrobenzene.

Development and validation of a prediction model of deep venous thrombosis for patients with acute poisoning following hemoperfusion: a retrospective analysis.

OBJECTIVE: To develop and confirm an individualized predictive model to ascertain the probability of deep venous thrombosis in patients with acute poisoning after undergoing hemoperfusion. METHODS: Three hundred eleven patients with acute poisoning who were admitted to a hospital in China between October 2017 and February 2019 were included in the development group. Eighty patients with acute poisoning who were admitted between February and May 2019 were included in the validation group. The independent risk factors for deep venous thrombosis were examined. An individualized predictive model was developed using regression coefficients. RESULTS: The number of catheter indwelling days, having a catheter while being transported, elevated serum homocysteine concentrations, and dyslipidemia were independent risk factors for deep venous thrombosis following hemoperfusion in patients with acute poisoning. The areas under the receiver operating characteristic curve of the development and validation groups were 0.713 and 0.702, respectively, which suggested that the prediction model had good discrimination capacity. The calibration belts of the two groups were ideal. CONCLUSIONS: Our prediction model has a moderate predictive effect for the occurrence of deep venous thrombosis in patients with acute poisoning. In clinical practice, this model could be combined with a common thrombosis risk assessment model.

Kidney and lung injury in rats following acute diquat exposure.

Diquat (1,1'-ethylene-2,2'-bipyridylium) is a type of widely used agricultural chemical, whose toxicity results in damage to numerous tissues, including the lung, liver, kidney and brain. The aim of the present study was to establish a rat model of acute diquat exposure and explore the relationship between diquat concentration, and kidney and lung injury, in order to provide an experimental basis for clinical treatment. A total of 140 healthy adult male Wistar rats were randomly divided into control and exposure groups. The diquat solution was administered intragastrically to the exposure group at 1/2 of the lethal dose (140 mg/kg). An equal volume of water was administered to the control group. The dynamic changes in the plasma and tissue diquat levels were quantitatively determined at 0.5, 1, 2, 4, 8, 16 and 24 h following exposure using liquid chromatography mass spectrometry. The content of hydroxyproline (HYP) in the lung tissues, as well as the levels of blood urea nitrogen (BUN), creatinine (Cr), uric acid (UA), kidney injury molecule-1 (KIM-1) and tumor growth factor (TGF)-ß1, were detected using western blot analysis at every time point. Lung and kidney morphology were also assessed. Electron microscopy showed that the degree of renal damage gradually increased with time. Vacuolation gradually increased, some mitochondrial bilayer membrane structures disappeared and lysosomes increased. The lung tissue damage was mild, and the cell membrane integrity and organelles were damaged to varying degrees. The plasma and organ levels of diquat peaked at ~2 h, followed by a steady decrease, depending on the excretion rate. Over time, the serum concentrations of UA, BUN, Cr and KIM-1 were all significantly increased (P<0.05). Serum KIM-1 in rats was increased after 0.5 h, and was significantly increased after 4 h, suggesting that KIM-1 is an effective predictor of early renal injury. Early TGF-ß1 expression was clearly observed in renal tissue, while no clear TGF-ß1 expression was observed in the lung tissue. In conclusion, the concentration of diquat in the serum and tissue of rats with acute diquat poisoning peaked at an early stage and then rapidly decreased. The renal function damage and pathological changes persisted, the lung tissue was slightly damaged with inflammatory cell infiltration, and early pulmonary fibrosis injury was not obvious.

A rare form of intoxication: acute methyl ethyl ketone peroxide poisoning.

We report two suicidal cases of acute methyl ethyl ketone peroxide (MEKP) poisoning. A woman in her late 60s suffered from oral mucosal erosion, functional impairment of the heart, liver and other organs, pulmonary inflammation, elevated inflammatory markers, pleural effusion, hypoproteinemia and metabolic acidosis after oral administration of approximately 50 mL of MEKP. After admission, the patient was administered hemoperfusion four times, 8 mg of betamethasone for 6 days and symptomatic support. Hemoperfusion had an obvious effect on the treatment of oral MEKP poisoning. After discharge, the patient developed progressive dysphagia and secondary esophageal stenosis. Supplementary feeding was administered with a gastrostomy tube after the patient was completely unable to eat. A man in his mid-40s developed oropharyngeal mucosal erosion, bronchitis and esophageal wall thickening after oral administration of 40 ml MEKP. After receiving total gastrointestinal dispersal, 80 mg of methylprednisolone was administered for 7 days, and symptomatic supportive treatment was provided. Slight dysphagia was observed after discharge, and there was no major effect on the quality of life. Patients with acute oral MEKP poisoning should be followed up regularly to observe its long-term effects on digestive tract corrosion and stenosis.

Acute diquat poisoning resulting in toxic encephalopathy: a report of three cases.

INTRODUCTION: Diquat-related acute kidney injury is well-known. However, neurological disorders caused by diquat are often underestimated, and changes in the imaging findings are rarely reported. We present three cases of acute diquat poisoning resulting in toxic encephalopathy. CASE REPORT: In the first case, a 20-year-old previously healthy man ingested approximately 80-100 mL of diquat. He developed acute renal failure, neurological disorders, and respiratory failure. Central pontine myelinolysis was considered by magnetic resonance imaging (MRI), 18 days after ingestion. In the second case, a 20-year-old man ingested approximately 100 mL of diquat. Toxic encephalopathy was confirmed by MRI, 13 days after ingestion. Unfortunately, he experienced cardiac arrest and died 18 days after ingestion. In the third case, a 31-year-old previously healthy man ingested approximately 50 mL of diquat. The imaging features of toxic encephalopathy mainly involved the medulla oblongata, pons, midbrain, bilateral brachium pontis, cerebellum, and pedunculus cerebri. He demonstrated significant recovery. DISCUSSION: Ingestion of diquat can cause acute renal failure, neurological disorders, and respiratory failure. The pons, midbrain, pedunculus cerebri may be the most commonly impaired locations of diquat-related toxic encephalopathy.

Hymenobacter terricola sp. nov., isolated from Antarctic soil.

Strain 3F2T was isolated from a soil sample obtained from the surface of Deception Island, Antarctica. The isolate was a Gram-stain-negative, aerobic, non-motile, rod-shaped bacterium, and its colonies were red to pink in colour. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 3F2T belonged to the genus Hymenobacter, family Hymenobacteraceae and was most closely related to Hymenobacter sedentarius DG5BT (97.0% sequence similarity), Hymenobacter soli PB17T (96.9%), Hymenobacter terrae DG7AT (96.8%) and Hymenobacter rufus S1-2-2-6T (96.5%). Growth occurred at 4-20 °C (optimum, 10 °C), up to 1.0 % (w/v) NaCl (optimum, 0%) and pH 6.0-8.0 (optimum, pH 7.0). The chemotaxonomic characteristics of strain 3F2T, which had MK-7 as its predominant menaquinone and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), iso-C15:0, anteiso-C15:0 and C16:1 ω5c as its major fatty acids, were consistent with classification in the genus Hymenobacter. The polar lipid profile of strain 3F2T comprised phosphatidylethanolamine, two unidentified aminolipids, two unidentified aminophospholipids and three unidentified polar lipids. The genome of strain 3F2T was 6.56 Mbp with a G+C content of 61.5 mol%. Average nucleotide identity (ANI) values between 3F2T and the other species of the genus Hymenobacter were found to be low (ANIm <87.0%, ANIb <82.0% and OrthoANIu <83.0%). Furthermore, digital DNA-DNA hybridization and average amino acid identity values between strain 3F2T and the closely related species ranged from 20.0 to 26.3% and from 64.0 to 81.1 %, respectively. Based on the results of our phylogenetic, phenotypic, genotypic and chemotaxonomic analyses, it is concluded that strain 3F2T represents a novel species within the genus Hymenobacter, for which the name Hymenobacter terricola sp. nov. is proposed. The type strain is 3F2T (=KCTC 72468T=CGMCC 1.13716T).

Actinotalea soli sp. nov., isolated from Kubuqi Desert soil.

A Gram-stain positive, facultatively anaerobic, motile rod-shaped strain, BY-33T, was isolated from a soil sample obtained from the Kubuqi Desert, PR China. Phylogenetic analysis based on 16S rRNA gene sequence similarity revealed that strain BY-33T was most closely related to the genus Actinotalea, including Actinotalea ferrariae CF5-4T (98.2 % similarity), 'Actinotalea subterranea' HO-Ch2T (98.0 %), Actinotalea solisilvae THG-T121T (97.6 %), 'Actinotalea bogoriensis' 69B4T (97.5 %), Actinotalea fermentans MT (97.3 %) and 'Actinotalea carbonis' T26T (97.0 %). The strain grew at 0‒37 °C (optimum, 28-30 °C) and pH 6.0-11.0 (optimum, pH 9.0-10.0) and with 0‒8.0 % (w/v) NaCl (optimum, 3.0%) on tryptic soy agar. It had catalase activity, but no oxidase activity. The polar lipids of strain BY-33T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, and phosphatidylinositol mannosides. The major respiratory quinone of strain BY-33T was MK-10 (H4). Its major fatty acids were anteiso-C15 : 0, anteiso-C15 : 1 A and C16 : 0. The genomic DNA G+C content of strain BY-33T was 73.0 mol% based on total genome calculations. The average nucleotide identity scores between the genomic sequences of strain BY-33T and the other species of the genus Actinotalea were found to be low (ANIm <85.0 %, ANIb <77.0 % and OrthoANIu <78.0 %). Furthermore, the digital DNA-DNA hybridization and average amino acid identity values between strain BY-33T and the closely related species ranged from 20.5 to 21.0% and from 62.2 to 72.2 %, respectively. Based on the results of phylogenetic, phenotypic, genotypic and chemotaxonomic analyses, it is concluded that strain BY-33T represents a novel species within the genus Actinotalea, for which the name Actinotalea soli sp. nov. is proposed. The type strain is BY-33T (=CGMCC 1.17460T=KCTC 49362T).

Treatment of Gastrointestinal Corrosive Burns Caused by Highly Lethal Glyphosate Solution Poisoning.

Glyphosate was developed by Monsanto in the United States in the 1870s and has now become the world's best-selling pesticide. It is used in more than 100 countries and regions. Glyphosate is generally considered to be less toxic or even safe for mammals, including humans, and most patients with glyphosate poisoning have a better prognosis. However, this article reports a case of a 36-year woman who suffered severe gastrointestinal damage after oral administration of 50 ml of glyphosate. After the active rescue, scar contractures occurred in both the ooesophagus and trachea. The patient recovered clinically after undergoing reconstructive surgery. Key Words: Glyphosate poisoning, Chemical burns, Ooesophageal reconstruction, Tracheal reconstruction.

Gluteal muscle damage and rhabdomyolysis after olanzapine poisoning: a case report.

Olanzapine is a widely adopted atypical antipsychotic medication used to manage schizophrenia. Reports show that the incidence rate of adverse reactions to olanzapine is significantly lower than those of other classic antipsychotic medications. However, olanzapine overdose may be associated with severe consequences. Herein, we report a 21-year-old female patient who had taken nearly 700 mg (70 tablets) of olanzapine; she was found after 30 hours. As her condition progressed, she presented with rhabdomyolysis, swelling in the thighs and hips, paralytic ileus, digestive tract hemorrhage, and elevated serum amylase and lipase levels; notably, she recovered after treatment. This intractable case is of great clinical significance and suggests that early-phase hemoperfusion plays a critical role in olanzapine poisoning-related rhabdomyolysis.

Secondary organizing pneumonia following occupational acute nitrogen oxide poisoning: a case report.

Secondary organizing pneumonia (SOP) is a nonspecific inflammatory response towards acute lung injuries caused by various diseases. However, organizing pneumonia (OP) secondary to occupational acute nitrogen oxide poisoning has been reported rarely. We report a 49-year-old man who suffered from nitrogen oxide poisoning after inhaling mixed gas at work. After pathological examination, he was diagnosed with OP. In the absence of other underlying factors causing OP, he was diagnosed with SOP owing to acute nitrogen oxide poisoning. After systematic treatment, the patient recovered and was discharged in better health. In patients with lung injury caused by acute nitrogen oxide poisoning, physicians should be alert to the risk of patients subsequently developing SOP, and timely diagnosis and treatment are essential for complete recovery.

Hydraulic resistance induces cell phenotypic transition in confinement.

Cells penetrating into confinement undergo mesenchymal-to-amoeboid transition. The topographical features of the microenvironment expose cells to different hydraulic resistance levels. How cells respond to hydraulic resistance is unknown. We show that the cell phenotype shifts from amoeboid to mesenchymal upon increasing resistance. By combining automated morphological tracking and wavelet analysis along with fluorescence recovery after photobleaching (FRAP), we found an oscillatory phenotypic transition that cycles from blebbing to short, medium, and long actin network formation, and back to blebbing. Elevated hydraulic resistance promotes focal adhesion maturation and long actin filaments, thereby reducing the period required for amoeboid-to-mesenchymal transition. The period becomes independent of resistance upon blocking the mechanosensor TRPM7. Mathematical modeling links intracellular calcium oscillations with actomyosin turnover and force generation and recapitulates experimental data. We identify hydraulic resistance as a critical physical cue controlling cell phenotype and present an approach for connecting fluorescent signal fluctuations to morphological oscillations.

Hyaluronic acid-shelled, peptide drug conjugate-cored nanomedicine for the treatment of hepatocellular carcinoma.

Peptide-drug conjugate (PDC) is a promising prodrug in drug delivery systems. To fabricate nanostructures with proper molecular design which can self-assemble to spherical morphologies is very important for PDC chemotherapy. In this study, a novel PDC (PDC-DOX2), in which two doxorubicin (DOX) molecules are conjugated onto a short peptide (KIGLFRWR) with self-assembly function, was designed and synthesized. PDC-DOX2 with self-assembly properties forms a spherical structure under hydrophobic interaction in water. Hyaluronic acid (HA) was then coated on PDC-DOX2 micelles to form a HA-shelled, peptide-doxorubicin conjugate-cored nanomedicine (HA@PDC-DOX2). The amount of HA can regulate the particle size and stabilization of HA@PDC-DOX2. In addition, HA can actively enhance the targeting effects of PDC-DOX2 micelles since it can interact with overexpressed receptors in cancer cells. The core-shell structured HA@PDC-DOX2 nanomedicine showed significantly enhanced potency against hepatocellular carcinoma compared to PDC-DOX2 micelles as well as free DOX. In this work, a novel PDC which can self-assemble to spherical morphologies and a core-shell structure HA@PDC-DOX2 nanomedicine are designed and prepared. It provides a convenient strategy for the size control of PDC assemblies and constructs effective PDC-based drug delivery systems for cancer treatment.