Investigation of the synergistic effect of melt-extension and nanofiller on the crystal-crystal phase transition from form II to I of isotactic polybutene-1.

New questions and conjectures are raised on the crystal-crystal phase transition of isotactic polybutene-1 (iPB-1) containing nanofiller in the flow field. In this work, we investigate the phase transition from flow-induced oriented form II to I in iPB-1 blends with multi-walled carbon nanotubes (MWCNTs) with a homemade two-drum extensional rheometer combined with in situ wide-angle X-ray diffraction (WAXD) measurements. The MWCNTs show a limited promoting effect on the phase transition kinetics under quiescent conditions, while the phase transition kinetic is highly accelerated with the impose of melt-extension. When the loading extension strain is 0.5 or 2.0, the half time of phase transition (t1/2) is shortened from tens of hours to a few hours, depending on the melt-extension strain and the MWCNTs content in iPB-1. When the extension strain increases to 3.5, t1/2 decreases to about 30 min, which is independent of the MWCNTs content in all iPB-1 blends except in blends with MWCNTs content of 1%, where the phase transition rate in the middle and late stages is restrained. It's speculated that flow-induced molecular orientation or shish-kebab morphology affects the internal stress or stress transfer. The addition of a nanofiller enlarged the effect of melt-extension through strengthening the localized intensity of flow field. In general, the combination of nanofiller and melt-extension can obviously promote the phase transition kinetics.

S-1 Maintenance Therapy in Extensive Stage Small-Cell Lung Cancer-A Randomized Clinical Study.

Small-cell lung cancer (SCLC) is a recalcitrant cancer for its dismal prognosis although extensive research had been done. Four to 6 cycles platinum-based chemotherapy is the mainstay treatment for the extensive-stage disease; but the role of maintenance treatment is not fully understood. This is a phase 2, open-label study. Patients with extensive-stage SCLC reaching an objective response or stable disease (SD) after induction chemotherapy were randomly assigned (1:1) with a minimization procedure. One group received oral S-1 and the other group received placebo as maintenance treatment until disease progression or unacceptable toxicities. The primary end point of this study was progression-free survival (PFS), and the secondary end points were overall survival (OS), response rates, and toxicities. This study was based on earlier work, the preliminary results was reported on 2019 ASCO annual meeting. A total of 89 patients were enrolled, of whom 45 received S-1 maintenance therapy and 44 received placebo. The median PFS and OS were 6.35 months and 10.82 months in the S-1 group, as compared to 5.98 months and 10.09 months in the placebo group. The PFS was 7.2 months and 5.3 months, and OS was 12.9 months and 10.9 months in patients with an objective response compared to in patients with SD after induction chemotherapy, respectively. S-1 maintenance therapy did not prolong PFS or OS in patients with extensive-stage SCLC; tumor regression rate was the prognostic factor of PFS or OS. Further research with novel agents in the maintenance setting is warranted.

Polymorph selection during melt crystallization of the isotactic polybutene-1 homopolymer depending on the melt state and crystallization pressure.

This work investigated the crystalline forms obtained from melt crystallization in the isotactic polybutene-1 (iPB-1) homopolymer via manipulation of the temperature at which samples were melted (Tmelt) and crystallization pressure (Pcry). Unlike the results under atmospheric conditions where the molten sample crystallized into the pure form II and the crystallization temperature and kinetics were affected obviously by Tmelt, the melted sample crystallized into forms II or I' under high pressure, depending on Tmelt and Pcry. The content of form I' decreases with increasing Tmelt or decreasing Pcry. Meanwhile, the critical pressure for the formation of pure form I' increases with increasing Tmelt. The formation of form I' is attributed to the memory effect of the melt which preserved some ordered sequence of crystal and the high pressure (Pcry) which suppressed the nucleation and growth of the kinetically favored form II, which results in the formation of form I'. In addition, the melt crystallized form II transforms to form I under high pressure conditions; thus forms I, I' and II are observed. The relative contents of the three crystalline forms on samples for different Tmelt and Pcry are obtained in this work. The result shows that the crystalline forms in melt crystallization of iPB-1 can be customized by regulating the melt state and crystallization conditions.

Bevacizumab Combined with Icotinib Overcomes Osimertinib Resistance in a Patient of Non-Small Cell Lung Cancer.

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor (EGFR) 19 del mutation positive. Treatment with icotinib was given, but her disease progressed after 6 months remission. CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis, and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) confirmed EGFR T790M mutation. Treatment with osimertinib was initiated. After 2 months remission, the disease progressed. Re-biopsy was performed for the tumor in the inferior lobe of left lung, and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del. Icotinib was re-challenged, but disease progressed continuously. Bevacizumab was added, and partial response was achieved after 2-cycle of combination therapy. The non-small cell lung cancer (NSCLC) in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment. This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.

Stretch-induced complexation reaction between poly(vinyl alcohol) and iodine: an in situ synchrotron radiation small- and wide-angle X-ray scattering study.

Fibrillation and the complexation reaction between poly(vinyl alcohol) (PVA)-iodine (i) complexes have been studied with in situ synchrotron radiation small- and wide-angle X-ray scattering (SAXS and WAXS) during the uniaxial stretching of PVA films in KI/I2 aqueous solution. SAXS results show that stretching induces the formation of nanofibrils, which pack periodically in the later stage of stretching with an average inter-fibrillar distance of around 10 nm. The onset strains for fibrillation and the appearance of periodicity of nanofibrils are located at the beginning and the end of the stress plateau, and decrease with increasing iodine concentration. In the stretching process as a whole, the presence of iodine ions reduces the crystallinity of the PVA crystal but favors the formation of a PVA-I complex. The complexation reaction is promoted by the synergistic effect of stretch and iodine ions, during which stretching drives the formation of polyiodine via the effect of entropic reduction while iodine concentration dictates crystallization of PVA-I3- co-crystals through the role of chemical potential. A morphological and structural phase diagram is constructed in the strain-iodine concentration space, which defines the regions for fibrillation and complexation reactions and may serve as a roadmap for the industrial processing of PVA polarizer.

Treatment of Skin Reaction Induced by Nivolumab Combined with Radiotherapy in Non-small Cell Lung Cancer: A Case Report.

Skin reaction or dermatological toxicities induced by immunotherapy is common. It usually manifests skin rash or erythema and can be cured by skin lotion or steroid. Nivolumab, a human IgG4 programmed cell death protein 1 (PD-1) inhibitor, blocks T cells activation preventing signal and allows the immune system to clear cancer cells. Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA, with less than 10% unusual skin reaction, like sensory neuropathy, peeling skin, erythema multiforme, vitiligo, and psoriasis. Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity. The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies, but the risk of side effects may be high. We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy. The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events. Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.

Structural and morphological transitions in extension-induced crystallization of poly(1-butene) melt.

Structural and morphological transitions of flow-induced crystallization (FIC) in poly(1-butene) (PB-1) melt have been studied by combining extensional rheology and in situ synchrotron radiation ultrafast wide- and small-angle X-ray scattering (WAXD/SAXS) measurements. Unexpectedly, metastable Form III is crystallized directly from the PB-1 melt by high-speed extension, which has a short lifetime of several tens of milliseconds and manifests the thermodynamic and kinetic competition among Form III, Form II and melt under flow. Relative crystallinity evolution of Form II after extension reveals a crystal melting dominated process within the observation time of 120 s even under high supercooling. This is opposite to the common case of FIC but supports the idea that flow alters the obtained crystal size and its thermodynamic stability. Additionally, a morphological transition from a flow-induced network to shish is observed by SAXS with increasing extension temperature from below to above the melting point of Form II. With above observations, we construct nonequilibrium structural and morphological diagrams of FIC in strain rate-temperature space, which may guide the industrial processing of the PB-1 material.

Coupling between intra- and inter-chain orderings in flow-induced crystallization of polyethylene: A non-equilibrium molecular dynamics simulation study.

Non-equilibrium molecular dynamics simulations have been performed to study the molecular mechanism of flow-induced crystallization (FIC) of polyethylene (PE). The end-to-end distance of chain Rete and the content of trans conformation Ctrans are extracted out to represent intra-chain conformation ordering at whole chain and segment levels, respectively, while orientation correlation function P, density ρ, and bond orientational order parameter Q4 are taken to depict inter-chain orders. Imposing the extension induces the intra-chain conformational ordering to occur first, which further couples with the inter-chain order and results in the formation of hexagonal packing. Further increasing strain leads to the appearance of orthorhombic order. The results demonstrate that the FIC of PE proceeds via a multi-stage ordering process, during which coupling occurs among stress, intra-chain conformation, and inter-chain orientation and density orderings. Analyzing the flow-induced energy evolution unveils that not only entropy but also energy plays an important role in the FIC.

Extensional Flow-Induced Dynamic Phase Transitions in Isotactic Polypropylene.

With a combination of fast extension rheometer and in situ synchrotron radiation ultra-fast small- and wide-angle X-ray scattering, flow-induced crystallization (FIC) of isotactic polypropylene (iPP) is studied at temperatures below and above the melting point of α crystals (Tmα). A flow phase diagram of iPP is constructed in strain rate-temperature space, composing of melt, non-crystalline shish, α and α&ß coexistence regions, based on which the kinetic and dynamic competitions among these four phases are discussed. Above Tmα , imposing strong flow reverses thermodynamic stabilities of the disordered melt and the ordered phases, leading to the occurrence of FIC of ß and α crystals as a dynamic phase transition. Either increasing temperature or stain rate favors the competiveness of the metastable ß over the stable α crystals, which is attributed to kinetic rate rather than thermodynamic stability. The violent competitions among four phases near the boundary of crystal-melt may frustrate crystallization and result in the non-crystalline shish winning out.

Clinical Observation of Bevacizumab Combined with S-1 in the Treatment of Pretreated Advanced Esophageal Carcinoma.

Objective To investigate the clinical effects and safety of bevacizumab combined with S-1 as the second-line treatment of recurrent and/or metastatic esophageal cancer after chemoradiation. Methods Patients with recurrent or metastatic esophageal cancer after chemoradiation were treated with bevacizumab and S-1. Bevacizumab was used by intravenous infusion, 7.5mg/kg body weight on day 1; S-1 was used by oral at 80mg/m2·d on day 1-14, 21 days as a cycle of treatment and repeated until either pro- gressive disease or intolerable toxicity occurred. Chest CT were performed and RECIST 1.1 was used for response evaluation. Kaplan-Meier method was used for survival analysis. Side effects were recorded and analyzed. Results Totally 78 patients were enrolled in the study, including 67 squamous cell carcinoma and 11 adenocarcinoma histologically. The overall response (CR+PR) rate was 22.4% (17/76) and disease control (CR+PR+SD) rate was 61.8% (47/76) respectively. The median follow-up time was 20 months (range from 9 to 44 months). The median progression-free survival (PFS) was 4.9 months (95% CI 4.4-5.5) and the median overall survival (OS) was 8.1 months (95% CI 7.6-9.2). The median PFS and OS of patients with metastasis diseases were 6.2 months (95% CI 3.3 to 6.3) and 8.5 months (95% CI 5.8 to 11.2), where PFS was longer than that of patients with local regional recurrence (median 5.0 months, 95% CI 3.0 to 5.5, P=0.017) and OS was longer than that of patients with regional disease and metastasis (median 8.0 months, 95% CI 4.6 to 9.5, P=0.010). The common adverse effects were mild to moderate neutropenia (84.2%), grade I-II hand and foot syndrome (51.3%), grade I-II nausea (48.7%), mild epistaxis (30.1%) and mild vomiting (14.5%). Esophageal bleeding occurred in 7.9% of patients. One patient (1.3%) died from massive bleeding which was caused by esophageal perforation. Conclusion Bevacizumab combined with S-1 was effective and safe for esophageal cancer patients who had recurrent or metastatic diseases after chemoradiation.

Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia.

BACKGROUND: Neuroinflammation is a key cascade after cerebral ischemia. Excessive production of proinflammatory mediators in ischemia exacerbates brain injury. Cold-inducible RNA-binding protein (CIRP) is a newly discovered proinflammatory mediator that can be released into the circulation during hemorrhage or septic shock. Here, we examine the involvement of CIRP in brain injury during ischemic stroke. METHODS: Stroke was induced by middle cerebral artery occlusion (MCAO). In vitro hypoxia was conducted in a hypoxia chamber containing 1% oxygen. CIRP and tumor necrosis factor-α (TNF-α) levels were assessed by RT-PCR and Western blot analysis. RESULTS: CIRP is elevated along with an upregulation of TNF-α expression in mouse brain after MCAO. In CIRP-deficient mice, the brain infarct volume, induction of TNF-α, and activation of microglia are markedly reduced after MCAO. Using microglial BV2 cells, we demonstrate that hypoxia induces the expression, translocation, and release of CIRP, which is associated with an increase of TNF-α levels. Addition of recombinant murine (rm) CIRP directly induces TNF-α release from BV2 cells and such induction is inhibited by neutralizing antisera to CIRP. Moreover, rmCIRP activates the NF-κB signaling pathway in BV2 cells. The conditioned medium from BV2 cells exposed to hypoxia triggers the apoptotic cascade by increasing caspase activity and decreasing Bcl-2 expression in neural SH-SY5Y cells, which is inhibited by antisera to CIRP. CONCLUSION: Extracellular CIRP is a detrimental factor in stimulating inflammation to cause neuronal damage in cerebral ischemia. GENERAL SIGNIFICANCE: Development of an anti-CIRP therapy may benefit patients with brain ischemia.

Sorafenib in liver function impaired advanced hepatocellular carcinoma.

OBJECTIVE: To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC). METHODS: In this three-center open-label study from November 2011 to May 2013, we randomly assigned 189 patients with advanced Child-Pugh class B or C HCC patients into two groups, one group with 95 patient to receive sorafenib (400 mg a time, twice a day) and the other group with 94 patients to receive best supportive care. The primary end points were progression-free survival and overall survival. RESULTS: The median progression-free survival was 2.2 months and 1.9 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.55; 95% confidence interval, 0.40-0.75; P=0.002). The median overall survival was 4.0 months and 3.5 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.48; 95% confidence interval, 0.35-0.68; P<0.001). The main adverse effect of sorafenib was rash and acne of the skin (in 51.7% patients). The incidences of severe rash, diarrhea, and dry skin were 5.6%, 5.6%, and 2.2% in the sorafenib group. One patient reached partial response in the sorafenib group. CONCLUSIONS: Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.

Osimertinib combined with bevacizumab as the first-line treatment in non-small cell lung cancer patients with brain metastasis harboring epidermal growth factor receptor mutations.

BACKGROUND: The efficacy and safety of osimertinib combined with bevacizumab in non-small cell lung cancer (NSCLC) patients with brain metastasis harboring epidermal growth factor receptor (EGFR) mutations have not been fully studied. METHODS: Treatment-naïve NSCLC patients with brain metastasis harboring EGFR-activating mutations were treated with osimertinib 80 mg oral daily and bevacizumab 15 mg/kg intravenously on day 1, repeated every 21 days, until disease progression, intolerable toxicity, or death. The primary endpoint was the median progression-free survival (mPFS), and the secondary endpoints were the median overall survival (mOS), response rates, and toxicities. This study has been registered in ClinicalTrials.gov (NCT05104281) and is ongoing. RESULTS: A total of 52 Chinese patients were enrolled, of whom 17 harbored EGFR 19 del and 35 harbored EGFR L858R mutation. The objective response rate (ORR) was 75.0% and the disease control rate (DCR) was 96.2%; the mPFS was 17.0 months (95% CI: 11.46-22.54), while the mOS was not reached. The mPFS was 20.0 months (95% CI: 14.56-25.44) and was 17.0 months (95% CI: 13.28-20.72) for patients harboring EGFR 19 del and EGFR L858R mutation (p = 0.844), respectively. The intracranial ORR was 82.7%, and the intracranial mPFS was 22.0 months (95% CI: 2.92-41.08).The main adverse events were mild-to-moderate hand-foot syndrome, diarrhea, hypertension, and proteinuria. Three patients developed grade III proteinuria, while five patients developed grade III hypertension; they permanently discontinued bevacizumab treatment. CONCLUSIONS: Osimertinib combined with bevacizumab shows promising results in EGFR-mutated NSCLC patients with brain metastasis, and the side effects are tolerable.

Prognostic Factors and Outcomes in Advanced Stage Lung Cancer Patients with COVID-19 Omicron Variant Infection.

Background: We study the characteristics and outcomes in lung cancer patients with COVID-19 Omicron variant infection. Methods: Hospitalized lung cancer patients with advanced-stage disease and laboratory-confirmed COVID-19 Omicron infection were included. Pneumonitis involving at least 25% of lung parenchyma on CT scans, accompanied by symptoms and oxygen saturation below 93%, were criteria for enrollment. Pneumonitis severity was graded using CTCAE v5.0. Treatment included Paxlovid, prednisolone, anticoagulation, and ventilation. Initial data, radiographic findings, and outcomes were compared. Logistic regression was employed to determine risk factors for in-hospital mortality. Results: Fifteen patients (median age: 65 years; 80.0% males) were included. 73.3% improved and were discharged, 20.0% died, and 6.7% remained intubated. Initial symptoms included cough (100.0%), fever (73.3%), and shortness of breath (53.3%). Symptoms resolved in discharged patients. Median fever duration was 3.5 days, and respiratory symptom recovery took 26 days. Three patients died due to respiratory failure from Omicron pneumonia. Lower oxygen saturation, reduced lymphocyte/neutrophil ratio on day 7, and diffuse bilateral lung lesions were poor prognostic factors. Conclusion: This study underscores the importance of prompt intervention and early diagnosis for lung cancer patients infected with the COVID-19 Omicron variant. Lower oxygen saturation, decreased lymphocyte/neutrophil ratio on day 7, and diffuse lung lesions on CT scans were associated with worse outcomes. Clinicians should prioritize timely and comprehensive management to improve survival rates in this population.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Ghrelin maintains the cardiovascular stability in severe sepsis.

BACKGROUND: Cardiovascular dysfunction, characterized by reduced cardiac contractility and depressed endothelium-dependent vascular relaxation, is common in severe sepsis. Although it is known that ghrelin produces beneficial effects following various adverse circulatory conditions, it remains unknown whether ghrelin increases cardiac contractility and improves vascular responsiveness to vasoactive agents in severe sepsis. METHODS: Male adult rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed mini-pump over 15 h. At 20 h after CLP (i.e., severe sepsis), the maximal rates of ventricular pressure increase (+dP/dt(max)) and decrease (-dP/dt(max)) were determined in vivo. In additional groups of animals, the thoracic aortae were isolated at 20 h after CLP. The aortae were cut into rings, and placed in organ chambers. Norepinephrine (NE) was used to induce vascular contraction. Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerine (NTG) were carried out. RESULTS: +dP/dt(max) and -dP/dt(max) decreased significantly at 20 h after CLP. Treatment with ghrelin significantly increased +dP/dt(max) and -dP/dt(max) by 36% (P < 0.05) and 35% (P < 0.05), respectively. Moreover, NE-induced vascular contraction and endothelium-dependent (ACh-induced) vascular relaxation decreased significantly at 20 h after CLP. Administration of ghrelin, however, increased NE-induced vascular contraction and ACh-induced vascular relaxation. In contrast, no significant reduction in NTG-induced vascular relaxation was seen in rats with severe sepsis irrespective of ghrelin treatment. CONCLUSIONS: Ghrelin may be further developed as a useful agent for maintaining cardiovascular stability in severe sepsis.

Peripheral administration of human adrenomedullin and its binding protein attenuates stroke-induced apoptosis and brain injury in rats.

Stroke is a leading cause of death and the primary medical cause of acquired adult disability worldwide. The progressive brain injury after acute stroke is partly mediated by ischemia-elicited inflammatory responses. The vasoactive hormone adrenomedullin (AM), upregulated under various inflammatory conditions, counterbalances inflammatory responses. However, regulation of AM activity in ischemic stroke remains largely unknown. Recent studies have demonstrated the presence of a specific AM binding protein (that is, AMBP-1) in mammalian blood. AMBP-1 potentiates AM biological activities. Using a rat model of focal cerebral ischemia induced by permanent middle cerebral artery occlusion (MCAO), we found that plasma levels of AM increased significantly, whereas plasma levels of AMBP-1 decreased significantly after stroke. When given peripherally early after MCAO, exogenous human AM in combination with human AMBP-1 reduced brain infarct volume 24 and 72 h after MCAO, an effect not observed after the treatment by human AM or human AMBP-1 alone. Furthermore, treatment of human AM/AMBP-1 reduced neuron apoptosis and morphological damage, inhibited neutrophil infiltration in the brain and decreased serum levels of S100B and lactate. Thus, human AM/AMBP-1 has the ability to reduce stroke-induced brain injury in rats. AM/AMBP-1 can be developed as a novel therapeutic agent for patients with ischemic stroke.

Upregulation of Kupffer cell α2A-Adrenoceptors and downregulation of MKP-1 mediate hepatic injury in chronic alcohol exposure.

Alcohol-induced liver disease is associated with unacceptable morbidity and mortality. When activated, Kupffer cells (KCs), the resident macrophages in the liver, release proinflammatory cytokine TNF-α, a key mediator of hepatic damage. Although chronic alcohol causes increase in norepinephrine (NE) release leading to hepatic dysfunction, the mechanism of NE-induced hepatic injury in chronic alcohol exposure has not been elucidated. This study was conducted to determine whether chronic alcohol exposure increases NE and upregulates KC α(2A)-adrenoceptors (α(2A)-AR) to cause TNF-α release. We also examined the role of mitogen activated protein kinase (MAPK) phosphatase-1 (MKP-1) in this process. Male adult rats were fed the Lieber-DeCarli liquid diet containing alcohol as 36% of total calories. The animals were sacrificed after 6 weeks and blood and liver samples were harvested for further analysis. KCs from healthy male rats were cultured with alcohol for 7 days, and cells then harvested for RNA and protein analyses. Chronic alcohol exposure resulted in hepatic damage. Alcohol caused a 276% increase in circulating NE and 86% increase in TNF-α in the liver. There was a 75% and 62% decrease in MKP-1 mRNA and protein levels, respectively in the liver. In-vitro experiments revealed 121% and 98% increase in TNF-α and α(2A)-AR mRNA levels with alcohol exposure, respectively, and a 32% decrease in MKP-1 mRNA compared to controls. In summary, chronic alcohol exposure elevates NE and upregulates KC α(2A)-AR to release TNF-α. Alcohol induced downregulation of MKP-1 leads to further release of TNF-α and hepatic injury.

Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor-factor VIII [corrected].

Sepsis, a highly lethal systemic inflammatory syndrome, is associated with increases of proinflammatory cytokines (e.g., TNF-alpha, HMGB1) and the accumulation of apoptotic cells that have the potential to be detrimental. Depending on the timing and tissue, prevention of apoptosis in sepsis is beneficial; however, thwarting the development of secondary necrosis through the active removal of apoptotic cells by phagocytosis may offer a novel anti-sepsis therapy. Immature dendritic cells (IDCs) release exosomes that contain milk fat globule EGF factor VIII (MFGE8), a protein required to opsonize apoptotic cells for phagocytosis. In an experimental sepsis model using cecal ligation and puncture, we found that MFGE8 levels decreased in the spleen and blood, which was associated with impaired apoptotic cell clearance. Administration of IDC-derived exosomes promoted phagocytosis of apoptotic cells and significantly reduced mortality. Treatment with recombinant MFGE8 was equally protective, whereas MFGE8-deficient mice suffered from increased mortality. IDC exosomes also attenuated the release of proinflammatory cytokines in septic rats. Liberation of HMGB1, a nuclear protein that contributes to inflammation upon release from unengulfed apoptotic cells, was prevented by MFGE8-mediated phagocytosis in vitro. We conclude that IDC-derived exosomes attenuate the acute systemic inflammatory response in sepsis by enhancing apoptotic cell clearance via MFGE8.

Development and validation of a prognostic nomogram for malignant esophageal fistula based on radiomics and clinical factors.

BACKGROUND: The current study aimed to comprehensively analyze the clinical prognostic factors of malignant esophageal fistula (MEF). Furthermore, this study sought to establish and validate prognostic nomograms incorporating radiomics and clinical factors to predict overall survival and median survival after fistula for patients with MEF. METHODS: The records of 76 patients with MEF were retrospectively analyzed. A stepwise Cox proportional hazards regression model was employed to screen independent prognostic factors and develop clinical nomograms. Radiomic features were extracted from prefistula CT images and post fistula CT images. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression algorithm was used to filter radiomic features and avoid overfitting. Radiomic signature was a linear combination of optimal features and corresponding coefficients. The joint prognostic nomograms was constructed by radiomic signatures and clinical features. All models were validated by Harrell's concordance index (C-index), caliberation and bootstrap validation. RESULTS: For overall survival, age, prealbumin, KPS and interval between diagnosis of esophageal cancer and fistula were identified as independent prognostic factors and incorporated into the clinical nomogram. Age, prealbumin, serum albumin, KPS and neutrophil proportion were selected for the clinical nomogram of post fistula survival. The C-index of overall survival nomogram was 0.719 (95% CI: 0.645-0.793) and that was 0.722 (95% CI: 0.653-0.791) in the post fistula survival nomogram. The radiomic signature developed by radiomic features of prefistula CT showed a significant correlation with both overall survival and post fistula survival. The C-index of joint nomogarm for overall survival and post fistula survival was 0.831 (95% CI: 0.757-0.905) and 0.77 (95% CI: 0.686-0.854), respectively. The calibration curve showed the joint nomograms outperformed the clinical ones. CONCLUSIONS: The study presents nomograms incorporating independent clinical risk factors and radiomic signature to predict the prognosis of MEF. This prognostic classification system has the potential to guide therapeutic decisions for patients with malignant esophageal fistulas.