[Clinical efficacy of induction chemoimmunotherapy for locally advanced hypopharyngeal carcinoma: a prospective phase â ¡ study].

Objective: To evaluate the objective response rate (ORR) of induction chemoimmunotherapy with camrelizumab plus TPF (docetaxel, cisplatin, and capecitabine) for locally advanced hypopharyngeal squamous cell carcinoma (LA HSCC) and potential predictive factors for ORR. Methods: A single-center, prospective, phase 2 and single-arm trial was conducted for evaluating antitumor activity of camrelizumab+TPF(docetaxel+cisplatin+capecitabine) for LA HSCC between May 21, 2021 and April 15, 2023, patients admitted to the Eye & ENT Hospital affiliated with Fudan University. The primary endpoint was ORR, and enrolled patients with LA HSCC at T3-4N0-3M0 received induction chemoimmunotherapy for three cycles: camrelizumab 200 mg day 1, docetaxel 75 mg/m2 day 1, cisplatin 25 mg/m2 days 1-3, and capecitabine 800 mg/m2 days 1-14. Patients were assigned to radioimmunotherapy when they had complete response or partial response (PR)>70% (Group A), or assigned to surgery plus adjuvant radiotherapy/chemoradiotherapy when they had PR≤70% (Group B), and the responses were defined by using tumor volume evaluation system. Tumor diameter was also used to assess the treatment responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Use SPSS 23.0 software was used to analyze the data. Results: A total of 51 patients were enrolled who underwent the induced chemoimmunotherapy for three cycles, and all were males, aged 35-69 years old. After three cycles of induction immunochemotherapy, 42 (82.4%) patients existed in Group A (complete response or PR>70%) and 9 patients (17.6%) in Group B (PR≤70%), the ORR was 82.4%. The primary endpoint achieved expected main research objectives. Compared to the patients of Group A, the patients of Group B showed the higher T stage and the larger volume of primary tumor before induced immunochemotherapy, and also had the less regression of tumor volume after induced immunochemotherapy (all P<0.05). The optimal cutoff value of pre-treatment tumor volume for predicting ORR was 39 cm3. The T stage (OR=12.71, 95%CI: 1.4-112.5, P=0.022) and the volume (OR=7.1, 95%CI: 1.4-36.8, P=0.018) of primary tumor were the two main factors affecting ORR rate of induction chemoimmunotherapy. Conclusion: The induction chemoimmunotherapy with camrelizumab plus TPF shows an encouraging antitumor efficacy in LA HSCC.

Del-1 enhances therapeutic efficacy of bacterial cancer immunotherapy by blocking recruitment of tumor-infiltrating neutrophils.

BACKGROUND: Bacterial-mediated cancer immunotherapy (BCI) elicits a more robust initial immune response than conventional immunotherapy, but does not prevent tumor recurrence and metastasis. BCI is associated with recruitment of tumor-infiltrating neutrophils, which could suppress the therapeutic efficacy of this modality. Development endothelial locus 1 (Del-1), a potent inhibitor of neutrophil recruitment, antagonizes lymphocyte function-associated antigen-1 on the vascular endothelium. Here, we aimed to determine the effect of Del-1-secreting S.t△ppGpp on anti-tumor activity and tumor-infiltrating neutrophil recruitment in a mouse model of colon cancer. METHODS: We investigated the anti-cancer activity of Del-1-secreting engineered Salmonella (△ppGpp S. Typhimurium) in the mice colon cancer models. RESULTS: In the present study, we identified that Del-1-secreting engineered Salmonella had more potent anti-cancer activity compared with normal S.t△ppGpp without Del-1 secretion. We postulated that Del-1 expression increased M1 macrophage recruitment to tumors by decreasing tumor-infiltrating neutrophils. This approach could enhance the anti-cancer effects of S.t△ppGpp. CONCLUSIONS: Collectively, the approach of using engineered bacteria that deliver Del-1 to block tumor-infiltrating neutrophil recruitment is a potential therapeutic approach.

Production and purification of 2-phenylethanol by Saccharomyces cerevisiae using tobacco waste extract as a substrate.

2-phenylethanol (2-PE), which is extracted naturally from plant or biotechnology processing, is widely used in the food and cosmetics industries. Due to the high cost of 2-PE production, the valorization of waste carbon to produce 2-PE has gained increasing attention. Here, 2-PE was produced by Saccharomyces cerevisiae using tobacco waste extract (TWE) as the substrate. Considering the toxicity of nicotine and its inhibition of 2-PE, the tolerance of S. cerevisiae was first evaluated. The results suggested that the production of 2-PE by S. cerevisiae in TWEs could be carried out at 2·0 mg ml-1 nicotine concentrations and may be inhibited by 1·0 mg ml-1 2-PE. Thus, the compounds in the TWEs prepared at different temperatures were detected, and the results revealed that the TWEs prepared at 140°C contained 2·18 mg ml-1 of nicotine, had total sugar concentrations of 26·8 mg ml-1 and were suitable for 2-PE production. Due to feedback regulation, the 2-PE production was only 1·11 mg ml-1 , and the remaining glucose concentration remained at 13·78 mg ml-1 , which indicated insufficient glucose utilization. Then, in situ product recovery was further implemented to remove this inhibition; the glucose utilization (the remaining concentration decreased to 3·64 mg ml-1 ) increased, and the 2-PE production increased to 1·65 mg ml-1 . The 2-PE produced in the fermentation broth was first isolated by elution from the resin with 75% ethanol and then by removing the impurities with 2·5% activated charcoal, and pure 2-PE was identified by gas chromatography mass spectrometry. The results of this study suggest that TWE could be an alternative carbon source for 2-PE production. This could provide an outlet tobacco waste as well as reducing the price of natural 2-PE, although more strategies need to be explored to improve the production yield of 2-PE by using TWE.

[Clinical effects of medical ozone autologous blood transfusion combined with Xingnaojing in the treatment of septic encephalopathy in burns].

Objective: To investigate the clinical effects of medical ozone autologous blood transfusion combined with Xingnaojing in the treatment of septic encephalopathy in burns. Methods: The retrospective cohort study was conducted. From August 2015 to May 2019, 90 patients with burn septic encephalopathy and conforming to the inclusion criteria were admitted to Zhengzhou First People's Hospital. Forty-six patients (25 males and 21 females, aged (35±4) years ) treated with Xingnaojing were included in Xingnaojing alone group, and forty-four patients (20 males and 24 females, aged (34±5) years) treated with medical ozone autologous blood transfusion combined with Xingnaojing were included in ozone autologous blood transfusion+Xingnaojing group. Heart rate, body temperature, mean arterial pressure, acute physiology and chronic health evaluation Ⅱ(APACHEⅡ) score and Glasgow coma score (GCS) of patients in 2 groups were recorded before treatment and on 7 d after treatment. The blood-brain barrier injury markers including occludin, nitric oxide synthase (NOS), neuron-specific enolase (NSE), central nervous system specific protein S100ß, glial fibrillar acidic protein (GFAP), and excitatory amino acid (EAA) in serum of patients in 2 groups were detected before treatment and on 1, 3, and 7 d after treatment. Computer tomography perfusion imaging for brain was performed in patients of 2 groups to calculate the region of interest cerebral blood flow (rCBF), region of interest blood volume (rCBV), and region of interest mean transit time (rMTT) before treatment and on 1, 3, and 7 d after treatment. Data were statistically analyzed with chi-square test, analysis of variance for repeated measurement, independent sample t test, and Bonferroni correction. Results: On 7 d after treatment, heart rate, body temperature, and mean arterial pressure of patients in 2 groups were decreased compared with those before treatment, heart rate of patients in ozone autologous blood transfusion+Xingnaojing group was obviously higher than that in Xingnaojing alone group (t=2.886, P<0.01), body temperature of patients in ozone autologous blood transfusion+Xingnaojing group was obviously lower than that in Xingnaojing alone group (t=5.020, P<0.01), and mean arterial pressure of patients in 2 groups were close (t=0.472, P>0.05). On 7 d after treatment, APACHEⅡ score of patients in ozone autologous blood transfusion+Xingnaojing group was obviously lower than that in Xingnaojing alone group (t=3.797, P<0.01), and GCS of patients in ozone autologous blood transfusion+Xingnaojing group was obviously higher than that in Xingnaojing alone group (t=4.934, P<0.01). On 3 and 7 d after treatment, the levels of occludin, NOS, NSE, S100ß, GFAP, and EAA in serum of patients in ozone autologous blood transfusion+Xingnaojing group were significantly lower than those in Xingnaojing alone group (t=2.100, 2.090, 2.691, 2.013, 2.474, 2.635, 2.225, 4.011, 3.150, 2.691, 3.145, 2.781, P<0.05 or P<0.01). On 1, 3, and 7 d after treatment, rCBF and rCBV of patients in ozone autologous blood transfusion+Xingnaojing group were significantly increased compared with those in Xingnaojing alone group (t=3.127, 3.244, 3.883, 7.274, 3.661, 2.777, P<0.01). On 7 d after treatment, rMTT of patients in ozone autologous blood transfusion+Xingnaojing group was (3.02±0.57) s, which was significantly lower than (3.11±1.20) s in Xingnaojing alone group (t=2.409, P<0.05). Conclusions: Transfusion of medical ozone autologous blood combined with Xingnaojing therapy can effectively relieve brain injury and improve cerebral blood perfusion in patients with burn septic encephalopathy, which is with safety and credibility.

Propofol and memory: a study using a process dissociation procedure and functional magnetic resonance imaging.

Thirty volunteers randomly received either mild or deep propofol sedation, to assess its effect on explicit and implicit memory. Blood oxygen level-dependent functional magnetic resonance during sedation examined brain activation by auditory word stimulus and a process dissociation procedure was performed 4 h after scanning. Explicit memory formation did not occur in either group. Implicit memories were formed during mild but not deep sedation (p = 0.04). Mild propofol sedation inhibited superior temporal gyrus activation (Z value 4.37, voxel 167). Deep propofol sedation inhibited superior temporal gyrus (Z value 4.25, voxel 351), middle temporal gyrus (Z value 4.39, voxel 351) and inferior parietal lobule (Z value 5.06, voxel 239) activation. Propofol only abolishes implicit memory during deep sedation. The superior temporal gyrus is associated with explicit memory processing, while the formation of both implicit and explicit memories is associated with superior and middle temporal gyri and inferior parietal lobule activation.

Ventrolateral prefrontal cortex is required for fear extinction in a modified delay conditioning paradigm in rats.

Recent evidence has demonstrated that the ventromedial prefrontal cortex (vmPFC) is a critical site of the neural circuits underlying fear extinction memory. The ventrolateral prefrontal cortex (vlPFC) is not directly involved in extinction processes within the aversive domain. However, most of the current cumulated data on extinction is based on a classical delay fear conditioning paradigm in which the interval between the onset of the conditioned stimulus (CS) and the unconditioned stimulus (US) is consistent in a given protocol. In the present study, we developed a modified delay fear conditioning paradigm in which the temporal distribution of the footshock US during the duration of the tone CS is programmed to be pseudorandom. Here, we examined the effects of electrolytic vmPFC and vlPFC lesions made before training on conditioned fear response in the modified paradigm. The behavioral procedure involved four sessions with a 24-h interval: habituation, fear conditioning, extinction training, and extinction test. Percent freezing to tone was assessed as a measure of conditioned fear response. The results show that neither vmPFC nor vlPFC lesions affect acquisition or extinction of conditioned fear response during the fear conditioning and extinction training sessions, respectively. During the extinction test session, both vmPFC- and vlPFC-lesioned rats showed deficits in the recall of the between-session extinction memory. The deficits could not be attributed to altered nonspecific responses (footshock sensitivity, locomotor activity, and nonspecific freezing response). Furthermore, vlPFC lesions made before training had no effect on conditioned fear response in the classical fear conditioning paradigm. These data suggest a preserved role of the vmPFC in fear extinction and a selective involvement of the vlPFC in extinction process in certain fear conditioning tasks.

Robust cellulosic ethanol production from SPORL-pretreated lodgepole pine using an adapted strain Saccharomyces cerevisiae without detoxification.

This study reports an ethanol yield of 270L/ton wood from lodgepole pine pretreated with sulfite pretreatment to overcome recalcitrance of lignocellulose (SPORL) using an adapted strain, Saccharomyces cerevisiae Y5, without detoxification. The enzymatic hydrolysate produced from pretreated cellulosic solids substrate was combined with pretreatment hydrolysate before fermentation. Detoxification of the pretreatment hydrolysate using overliming or XAD-4 resin before being combined with enzymatic hydrolysate improved ethanol productivity in the first 4h of fermentation and overall fermentation efficiency. However, detoxification did not improve final ethanol yield because of sugar losses. The Y5 strain showed excellent ethanol productivities of 2.0 and 0.8g/L/h averaged over a period of 4 and 24h, respectively, in the undetoxified run. The furan metabolization rates of the Y5 strain were significantly higher for the undetoxified run than those for the detoxidfied runs, suggesting it can tolerate even higher furan concentrations than those studied. Preliminary mass and energy balances were conducted. SPORL produced an excellent monomeric sugar recovery value of about 85% theoretical and a net energy output of 4.05GJ/ton wood with an ethanol energy production efficiency of 178% before distillation.

Effect of midazolam on memory: a study of process dissociation procedure and functional magnetic resonance imaging.

To assess the effects of midazolam on explicit and implicit memories, 12 volunteers were randomly divided into the two groups: one with an Observer's Assessment of Alertness/Sedation score of 3 (mild sedation) and one with a score of 1 (deep sedation). Blood oxygen-level-dependent functional magnetic resonance imaging was measured before and during an auditory stimulus, then with midazolam sedation, and then during a second auditory stimulus with continuous midazolam sedation. After 4 h, explicit and implicit memories were assessed. There was no evidence of explicit memory at the two levels of midazolam sedation. Implicit memory was retained at a mild level of midazolam sedation but absent at a deep level of midazolam sedation. At a mild level of midazolam sedation, activation of all brain areas by auditory stimulus (as measured by functional magnetic resonance imaging) was uninhibited. However, a deep level of midazolam sedation depressed activation of the superior temporal gyrus by auditory stimulus. We conclude that midazolam does not abolish implicit memory at a mild sedation level, but can abolish both explicit and implicit memories at a deep sedation level. The superior temporal gyrus may be one of the target areas.

Hydrazinonaphthalene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis.

High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM.

[Studies on the circulated edition of Shang Han Lun in pre -Song period and its collation and systematization].

By comparing the Song edition of Shang Han Lun with that of the pre -Song period, it is claimed that the original order of this book was not arranged on the sequence of 3- yin and 3- yang. Instead, it is arranged on the sequence of indications and contraindications of diaphoresis, emesis, purgation. During the process of its circulation, it was separated into two stems of circulated edition, the Shang Han Lun and Jin Gui Yu Han Jing, and the system of 3- yin and 3- yang, order of entries diagnosis based on differentiation of 6 channels, and polish of languages were completed during the process of its circulation. The edition collated by Lin Yi of the Song dynasty was the one circulated until today.

Determination of quinolizidine alkaloids in traditional Chinese herbal drugs by nonaqueous capillary electrophoresis.

A rapid method for the determination of quinolizidine alkaloids by nonaqueous capillary electrophoresis was developed. A total of 10 alkaloids (matrine, sophocarpine, oxymatrine, oxysophocarpine, sophoridine, cytisine, sophoramine, aloperine, lehmannine and dauricine) could be easily separated within 18 min. A running buffer composed of 50 mM ammonium acetate, 10% tetrahydrofuran and 0.5% acetic acid in methanol was found to be the most suitable for this separation. Five of these alkaloids were selected for further studies. The linear calibration ranges were 2.51-50.1 microg/ml for sophoridine and sophocarpine, 2.71-54.2 microg/ml for matrine, 3.30-65.9 microg/ml for oxymatrine, and 3.10-62.0 microg/ml for oxysophocarpine. The recovery of the five alkaloids was 98.0-101.3% with relative standard deviations from 1.03 to 2.68% (n=5). The limits of detection for all 10 alkaloids were over the range 0.93-2.31 microg/ml. The method was successfully applied to the phytochemical analysis of alkaloid extracts from three commonly used traditional Chinese herbal drugs: Sophora flavescens Ait. (Kushen), S. alopecuroides L. (Kudouzi or Kugancao) and S. tonkinensis Gapnep (Shandougen).

[Identification study on pig's hoofnail].

The identification characteristics of pig's hoofnail on properties and tissue slice was initially probed from the viewpoint of identification in this paper in order to make basis for the systematic research on replacing Squama manitis.

[Capsaicin-sensitive afferent neurons and endogenous nitric oxide (NO) mediate the gastric acid secretion and hyperemic responses to intragastric peptone].

Using hydrogen gas clearance technique to measure gastric mucosal blood flow (GMBF) and a high dose of capsaicin to ablate the capsaicin-sensitive afferent neurons, the role of capsaicin-sensitive neurons in the gastric acid secretion and hyperemic response to intragastric peptone was investigated. The results were as follows: (1) there was an increase in acid secretion associated with the hyperemic response to intragastric peptone; (2) pretreatment with a high dose of capsaicin to ablate afferent neurons completely abolished the gastric hyperemic response to intragastric peptone and partially inhibited the acid secretion; (3) the gastric hyperemic response to intragastric peptone was completely blocked by pretreatment with L-nitro-arginine methyl ester (L-NAME), whereas the acid secretion was significantly attenuated; (4) inhibited effects of L-NAME on acid secretion and GMBF could be reversed by pretreatment with L-arginine (L-ARG); (5) pretreatment with atropine inhibited gastric acid output (GAO) and partially attenuated GMBF. These results suggested that capsaicin-sensitive afferent neurons and endogenous NO were involved in the gastric acid secretion and hyperemic response to intragastric peptone and the hyperemic response was mediated by both cholinergic and noncholinergic neurons.

[Answers to queries on absence of "heart related to fire" theory in the western Han Dynasty].

This paper claims that all the materials, including the first chapter of Lu's Chun Qiu Shi Er Ji, the theory of Heart Related to Fire in Huai Nan Zi Di Xing Xun, and "Chi Di Zi kills Bai Di Zi" are all later interpolations and are, therefore, unconvincing. The author offers ten questions conflicting with the old sayings.

[A study on Mechanism of prevention and treatment of gastric ulcer with Os sepiella in rats].

The Os Sepiella maiudrone (OSM) could markedly inhibit the stress-induced gastric mucosal lesions and promote the healing of acetic acid-induced gastric ulcer in rats were reported previously. In order to demonstrate its mechanism, the effects of OSM on acidity of gastric juice, combined mucus content in gastric wall, DNA synthesis, gastric movements, the gastric contents of prostaglandin E2 (PGE2) and cAMP of gastric tissue were examined. The results showed that OSM could neutralize the gastric acid, promote the production of cAMP and PGE2 in gastric tissue. These suggested that the neutralization of gastric acid and enhancing the gastric mucosal cytoprotection by OSM would play a role in preventing and curing gastric ulcers in rats.

[Transportation trends after rat renal intracapsular injection of Salvia miltiorrhizae].

The concentration of Salvia miltiorrhizae (SM) was detected at different time after renal intracapsular injection in S.D rats. It showed that SM concentration was higher in kidney than in plasma (P < 0.05). SM concentration in kidney increased gradually, it reached the peak at 24 hour and still remained in higher level at 48 hour. The SM injected in renal capsule could be passively transported to renal tissue and maintained at a high level. This result demonstrated that renal intracapsular injection could be applied as an important therapeutical method for different renal disease.

[HPTLC densitometric determination of free bile acids in bezoar].

Cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) which are extracted with CH3OH from Bezoar can be separated on HPTLC silica gel plate (made in China) with isooctane-n-butyl acetate-acetic acid (4:2:1), and the three bile acids were determined by TLC densitometry.