[Application of Midline Catheter Placed Under Ultrasound Guidance in Intravenous Therapy for Oral and Maxillofacial Tumor].

Objective: To examine the application effect of ultrasound-guided placement of midline catheter and to select the appropriate placement method of intravenous catheter for patients with oral and maxillofacial tumors. Methods: We retrospectively analyzed the general data and venous catheter-related information of 143 oral and maxillofacial tumor patients who received treatment between June 2019 and December 2021. There were two patient groups, a control group of patients with inserted peripheral venous catheters (PVC) and an observation group of patients with midline catheters placed under ultrasound guidance. We made a comparative analysis of the incidence of catheter-related complications, including bleeding at the insertion site, phlebitis, catheter blockage, extravasation, etc., in the two groups. When the baseline data from the two groups were not balanced, we used propensity score matching (PSM) to match the general data before comparing the complication incidence between the two groups. Results: There were 71 patients who underwent 215 times of PVC placement in the control group and 72 patients who underwent 72 times of midline catheter placement in the observation group. There was no significant difference between the patients in the two groups in terms of age, sex, diagnosis, or the use of anticoagulant medication ( P>0.05) . The observation group had longer average length-of-stay than the control group did ( P<0.01). The cost of catheter placement in the observation group was 1080 yuan per set, with the average daily cost being about (56.27±20.23) yuan. Patients in the control group had PVC placement for an average of (3.03±0.93) times. The cost for PVC placement was 96 yuan per time and the average daily cost was about (19.94±7.50) yuan. There was significant difference in the average daily cost between the observation group and the control group ( P<0.01). PSM was performed for the two groups. Before PSM, the incidence of catheter-related complications in the observation group (8.3%, 6/72) was lower than that of the control group (30.2%, 65/215) and the difference was statistically significant ( P<0.01). After PSM, 72 times of catheter placement from each group were included in comparative analysis. The incidence of catheter-related complications in the observation group (8.3%, 6/72) was lower than that of the control group (54.2%, 39/72) and the difference was statistically significant ( P<0.01). Conclusion: Patients have low incidence of catheter-related complications when they have midline catheter placed under ultrasound guidance, which helps reduce the pain of repeated venous insertion that patients incur and the workload of clinical nurses. The use of midline catheters is appropriate for and should be popularized among patients with oral and maxillofacial malignant tumors, especially patients who have poor peripheral venous conditions and those who are undergoing repair and reconstruction surgeries.

A new AAV tool for highly preferentially targeting hippocampal CA2.

Mice hippocampus contains three prominent subregions, CA1, CA3 and DG and is well regarded as an essential multiple task processor for learning, memory and cognition based on tremendous studies on these three subregions. The narrow region sandwiched between CA1 and CA3 called CA2 has been neglected for a long time. But it raises great attentions recently since this region manifests the indispensable role in social memory. Its unique physical position connecting CA1 and CA3 suggests the potential novel functions besides social memory regulation. But the CA2 is too small to be accurately targeted. A flexible AAV tool capable of accurately and efficiently targeting this region is highly demanded. To fill this gap, we generate an AAV expressing Cre driven by the mini Map3k15 promoter, AAV/M1-Cre, which can be easily utilized to help tracing and manipulating CA2 pyramidal neurons. However, M1-Cre labeled a small percentage of M1+RGS14- neurons that do not colocalize with any RGS14+/STEP+/PEP4+/Amigo2+ pyramidal neurons. They are proved to be the mixture of normal CA2 pyramidal neurons, CA3-like neurons in CA2-CA3 mixed border, some CA2 interneurons and rarely few CA1-like neurons, which are probably the ones projecting to the revealed CA2 downstream targets, VMH, STHY and PMV in WT mice injecting this AAV/M1-Cre virus but not in Amigo2-Cre mice. Though it is still challenging to get a pure CA2 tracking and manipulation system, this tool provides a new, more flexible and extended strategy for in-depth CA2 functional study in the future.

Clinicopathologic features and molecular analysis of enterovirus 71 infection: report of an autopsy case from the epidemic of hand, foot and mouth disease in China.

A 15-month boy with fatal hand, foot, and mouth disease (HFMD) exhibited atypical symptoms and progressed rapidly to death. An autopsy was performed the next day and tissue sections were stained for histopathological examination. His intestinal samples were tested for enterovirus 71 (EV71), and the whole-genome sequence of EV71 was analyzed. An autopsy revealed that the central nervous system, lungs, and gut displayed severe meningitis and brainstem encephalitis, remarkable pulmonary congestion, edema, moderate inflammatory infiltration, and hemorrhage as well as intestinal mucosal congestion, epithelial necrosis, thinning intestinal wall, and submucosal lymphoid follicular hyperplasia. The heart showed myocardial interstitial congestion, myocardial edema, and some inflammatory infiltrates. There were no significant alterations in the architecture of other organs. EV71 antigen and apoptotic cells were detected in brain, lung and intestine by immunohistochemical staining and TUNEL (TdT-mediated dUTP nick-end labeling) respectively. Intestinal contents and intestinal autopsy samples of this case were positive for EV71, and the EV71 strain was classified as subgenogroup C4. In China, the severe forms of HFMD were mostly caused by EV71 subgenogroup C4 infection. Severe intestinal damages may relate to EV71 subgenogroup C4 infection. Thus, children with severe EV71 HFMD may have serious pathological changes in their central nervous system, lungs, and gut. Physicians should pay special attention to infants with atypical symptoms, particularly in EV71 epidemic areas for early diagnosis and treatment.

Decontamination of surgical face masks and N95 respirators by dry heat pasteurization for one hour at 70°C.

BACKGROUND: The need for protective masks greatly exceeds their global supply during the current COVID-19 pandemic. METHODS: We optimized the temperature used in the dry heat pasteurization method to destroy pathogens and decontaminate masks while retaining their filtering capacity. RESULTS: The current study showed that dry heat at both 60°C and 70°C for 1 hour could successfully kill 6 species of respiratory bacteria and one fungi species, and inactivate the H1N1 indicator virus. After being heated at 70°C for 1, 2, and 3 hours, the N95 respirators and surgical face masks showed no changes in their shape and components. The filtering efficiency of bacterial aerosol for N95 respirators were 98%, 98%, and 97% after being heated for 1, 2, and 3 hour, respectively, all of which were over the 95% efficiency required and similar to the value before being heated (99%). The filtering efficiency for surgical face masks was 97%, 97%, and 96% for 1, 2, and 3 hours of heating, respectively, all of which were also similar to the value before being heated (97%). CONCLUSIONS: This method can be used at home and can significantly resolve the current shortage of masks.

Investigation of novel 7,8-disubstituted-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones as potent Chk1 inhibitors.

The synthesis and structure-activity relationships (SAR) of Chk1 inhibitors based on a 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one core are described. Specifically, an exploration of the 7 and 8 positions on this previously disclosed core afforded compounds with improved enzymatic and cellular potency.

Involvement of the nitric oxide in melatonin-mediated protection against injury.

Melatonin is a hormone mainly synthesized by the pineal gland in vertebrates and known well as an endogenous regulator of circadian and seasonal rhythms. It has been demonstrated that melatonin is involved in many physiological and pathophysiological processes showing antioxidant, anti-apoptotic and anti-inflammatory properties. Nitric oxide (NO) is a free radical gas in the biological system, which is produced by nitric oxide synthase (NOS) family. NO acts as a biological mediator and plays important roles in different systems in humans. The NO/NOS system exerts a broad spectrum of signaling functions. Accumulating evidence has clearly revealed that melatonin regulates NO/NOS system through multiple mechanisms that may influence physiological and pathophysiological processes. This article reviews the latest evidence for the effects of melatonin on NO/NOS regulation in different organs and disease conditions, the potential cellular mechanisms by which melatonin is involved in organ protection are discussed.

Peripheral sympathetic mechanisms in orofacial pain.

Sympathetic nervous system (SNS) is a part of the autonomic nervous system which involuntarily regulates internal body functions. It appears to modulate the processing of nociceptive information. Many orofacial pain conditions involve inflammation of orofacial tissues and/or injury of nerve, some of which might be attributed to SNS. Thus, the aim of this review was to bring together the data available regarding the peripheral sympathetic mechanisms involved in orofacial pain. A clearer understanding of SNS-sensory interactions in orofacial pain may provide a basis for novel therapeutic strategies for conditions that respond poorly to conventional treatments.

Activation of satellite glial cells in trigeminal ganglion following dental injury and inflammation.

Satellite glial cells (SGCs), a peripheral neuroglial cell, surround neurons and form a complete envelope around individual sensory neurons in the trigeminal ganglia (TG), which may be involved in modulating neurons in inflammation. The purpose of this study was to determine the effect of dental injury and inflammation on SGCs in the TG. Pulp exposure (PX) was performed on the first maxillary molar of 28 rats. The neurons innervating injured tooth in TG were labeled by the retrograde transport of fluoro-gold (FG). Specimens were collected at 1, 3, 7, 14, 21 and 28 days after PX and stained immunohistochemically for glial fibrillary acid protein (GFAP), a marker of SGCs activation, in the TG. We observed that GFAP-immunoreactivity (IR) SGCs enclosed FG-labeled neurons increased in a time-dependent manner after PX. The neurons surrounded by GFAP-IR SGCs were mainly small and medium in size. The GFAP-IR SGCs encircled neurons increased significantly in the maxillary nerve region of the TG at 7-28 days following PX. The results show that dental injury and inflammation induced SGCs activation in the TG. It indicates that activation of SGCs might be implicated in the peripheral mechanisms of pain following dental injury and inflammation.

Design, synthesis, and biological activity of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one-based potent and selective Chk-1 inhibitors.

A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.

Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.

A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).

[Epidemiological and etiological characteristics of hand-foot-mouth disease in Ningbo, Zhejiang province, 2008-2011].

OBJECTIVE: To analyze the epidemiological characteristics of hand foot and mouth disease (HFMD) in Ningbo. METHODS: A descriptive analysis was conducted through the surveillance data of HFMD in Ningbo, Zhejiang province, from 2008 to 2011. Genes on EV71 and Cox A16 were amplified with RT-PCT from the stool samples of HFMD patients. Sequences were analyzed by bioinformatics software. RESULTS: 37 524 cases of HFMD were reported from 2008 to 2011, including 196 severe cases and 12 deaths. The reported incidence was 145.26 per 100 000 and the case fatality was 0.03%. Cases in children aged 5 or younger accounted for 95.89%, and the scattered cases accounted for 64.10%. Xiangshan and Ninghai counties had the highest incidence rates in Ningbo. The peak of incidence was from April to July. The number of male patients was obviously higher than females. 2394 cases of HFMD were laboratory confirmed and EV71 with the predominant epidemic strain. Data from phylogenetic analysis revealed that EV71 isolated from HFMD patients in Ningbo belonged to C4a evolution branch of C4 sub-genotype, with several transmission chains. Cox A16 belonged to B1 evolution branch. 53.48% of the healthy children in Ningbo showed EV71 antibody positive. The geometric mean of the antibody titer (GMT) was 11.23 (8.33 - 14.98) in healthy children. Cox A16 antibody was detected at 63.18% of the healthy children in Ningbo. GMT in healthy children was 12.61 (6.70 - 16.52). CONCLUSION: HFMD was highly endemic in Ningbo, with children under 5 years old were at high-risk. The major etiologic agent was EV71 which belonged to C4a in the C4 sub-genotypes. Cox A16 belonged to the B1 evolution branch, which were in line with the predominant virus circulating in the mainland of China.

Epidemiological and etiological characteristics of hand, foot, and mouth disease in Ningbo, China, 2008-2011.

BACKGROUND: Outbreaks of hand, foot, and mouth disease (HFMD) in central China have caused public health concerns since 2007. It is of particular public health significance to update epidemiology of HFMD in port cities. OBJECTIVE: To investigate epidemical, etiological and clinical characteristics of HFMD in Ningbo, China, from 2008 to 2011. STUDY DESIGN: From May 2008 to December 2011, a total of 37,404 HFMD cases including 196 severe and 12 fatal cases were investigated. Human enteroviruses from 2360 cases were determined by real-time RT-PCR. The VP1 gene of EV71 from 78 cases and CA16 from 21 cases, the VP4 gene from 28 cases, and full-length genomes of 10 isolates were analyzed. Neutralizing antibodies were evaluated in 258 healthy subjects. Parameters associated with severe HFMD were evaluated. RESULTS: Annual incidence of HFMD was 3066.8/100,000 in the population of ≤5 years. EV71 C4a, CA16 B1, and other enteroviruses accounted for 63.7%, 24.0% and 12.3%, respectively. The genomes of EV71 from fatal and non-fatal cases were nearly identical. The positive rates of neutralizing antibody to EV71 increased from 13.5% to 67.6% in 1- to 5-year healthy groups. The neutralizing antibody to CA16 B1 isolate was negative. EV71, exposure history and certain early manifestations including fever, vomiting, limb exanthema and peripheral neutrophil ratio were significantly associated with HFMD severity. CONCLUSIONS: HFMD mainly caused by EV71 C4a and CA16 B1 is seriously epidemic in Ningbo. Future emphasis should be paid on EV71 immuno-prophylaxis and early identification of severe cases upon the etiological and clinical characteristics.

Cyclin B1 is an efficacy-predicting biomarker for Chk1 inhibitors.

Chk1 is the major mediator of cell-cycle checkpoints in response to various forms of genotoxic stress. Although it was previously speculated that checkpoint abrogation due to Chk1 inhibition may potentiate the efficacy of DNA-damaging agents through induction of mitotic catastrophe, there has not been direct evidence proving this process. Here, through both molecular marker and morphological analysis, we directly demonstrate that specific downregulation of Chk1 expression by Chk1 siRNA potentiates the cytotoxicities of topoisomerase inhibitors through the induction of premature chromosomal condensation and mitotic catastrophe. More importantly, we discovered that the cellular cyclin B1 level is the major determinant of the potentiation. We show that downregulation of cyclin B1 leads to impairment of the induction of mitotic catastrophe and correspondingly a reduction of the potentiation ability of either Chk1 siRNA or a small molecule Chk1 inhibitor. More significantly, we have extended the study by examining a panel of 10 cancer cell-lines with different tissue origins for their endogenous levels of cyclin B1 and the ability of a Chk1 inhibitor to sensitize the cells to DNA-damaging agents. The cellular levels of cyclin B1 positively correlate with the degrees of potentiation achieved. Of additional interest, we observed that the various colon cancer cell lines in general appear to express higher levels of cyclin B1 and also display higher sensitivity to Chk1 inhibitors, implying that Chk1 inhibitor may be more efficacious in treating colon cancers. In summary, we propose that cyclin B1 is a biomarker predictive of the efficacy of Chk1 inhibitors across different types of cancers. Unlike previously established efficacy-predictive biomarkers that are usually the direct targets of the therapeutic agents, cyclin B1 represents a non-drug-target biomarker that is based on the mechanism of action of the target inhibitor. This finding may be potentially very useful for the stratification of patients for Chk1 inhibitor clinical trials and hence, maximize its chance of success.

Discovery of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of potent and selective checkpoint kinase 1 inhibitors.

A new class of checkpoint kinase 1 (CHK-1) inhibitors bearing a 1,4-dihydroindeno[1,2-c]pyrazole core was developed after initial hits from high throughput screening. The efficient hit-to-lead process was facilitated by X-ray crystallography and led to potent inhibitors (<10nM) against CHK-1. X-ray co-crystal structures of bound inhibitors demonstrated that two sub-series of this class of compounds, exemplified by 21 and 41, exhibit distinctive hydrogen bonding patterns in the specificity pocket of the active site. Two compounds, 41 and 43, were capable of potentiating doxorubicin and camptothecin, both DNA-damaging agents, in cell proliferation assays (MTS and soft agar assays) and abrogating G2/M checkpoint in a mechanism-based FACS assay.

Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics.

The majority of cancer therapeutics induces DNA damage to kill cells. Normal proliferating cells undergo cell cycle arrest in response to DNA damage, thus allowing DNA repair to protect the genome. DNA damage induced cell cycle arrest depends on an evolutionarily conserved signal transduction network in which the Chk1 kinase plays a critical role. In mammalian cells, the p53 and RB pathways further augment the cell cycle arrest response to prevent catastrophic cell death. Given the fact that most tumor cells suffer defects in the p53 and RB pathways, it is likely that tumor cells would depend more on the Chk1 kinase to maintain cell cycle arrest than would normal cells. Therefore Chk1 inhibition could be used to specifically sensitize tumor cells to DNA-damaging agents. We have previously shown that siRNA-mediated Chk1 knockdown abrogates DNA damage-induced checkpoints and potentiates the cytotoxicity of several DNA-damaging agents in p53-deficient cell lines. In this study, we have developed 2 potent and selective Chk1 inhibitors, A-690002 and A-641397, and shown that these compounds abrogate cell cycle checkpoints and potentiate the cytotoxicity of topoisomerase inhibitors and gamma-radiation in p53-deficient but not in p53-proficient cells of different tissue origins. These results indicate that it is feasible to achieve a therapeutic window with 1 or more Chk1 inhibitors in potentiation of cancer therapy based on the status of the p53 pathway in a wide spectrum of tumor types.

Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.

Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.

Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.

A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.

Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase.

A non-methionine FT inhibitor lead structure (1) was designed through computer modeling of the peptidomimetic FT inhibitor ABT839. Optimization of this lead resulted in compounds 2e and 2g, with FT IC(50) values of 1.3 and 1.8 nM, GGT IC(50) of 1400 nM, and EC(50) (Ras processing) values of 13 and 11 nM, respectively.

A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies.

Ras mutation has been detected in approximately 20-30% of all human carcinomas, primarily in pancreatic, colorectal, lung and bladder carcinomas. The indirect inhibition of Ras activity by inhibiting farnesyltransferase (FTase) function is one therapeutic intervention to control tumor growth. Here we report the preclinical anti-tumor activity of our most advanced FTase inhibitor (FTI), ABT-100, and a direct comparison with the current clinical candidates. ABT-100 is a highly selective, potent and orally bioavailable FTI. It broadly inhibits the growth of solid tumors in preclinical animal models. Thus, ABT-100 is an attractive candidate for further clinical evaluation. In addition, our results provide plausible insights to explain the impressive potency and selectivity of ABT-100. Finally, we have demonstrated that ABT-100 significantly suppresses the expression of vascular endothelial growth factor (VEGF) mRNA and secretion of VEGF protein, as well as inhibiting angiogenesis in the animal model.

Synthesis and biological evaluation of 4-[3-biphenyl-2-yl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile as novel farnesyltransferase inhibitor.

Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anti-cancer agents. Analogues of the potent FTI, 4-[3-biphenyl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile, were synthesized and tested in vitro for their inhibitory activities. The synthesis and detailed biological data of this series of analogues are presented.