Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

The in vitro mechanism of Vaspinregulates the proliferation and steroidogenesis of rat lutein cells.

OBJECTIVE: Stable luteal cell function is an important prerequisite for reproductive ability and embryonic development. However, luteal insufficiency seriously harms couples who have the desire to have a pregnancy, and the most important thing is that there is no complete solution. In addition, Vaspin has been shown to have regulatory effects on luteal cells, but the complex mechanisms involved have not been fully elucidated. Therefore, this study aimed to explore the effect of Vaspin on rat luteal cells and its mechanism. METHODS: Granulosa lutein cells separated from the ovary of female rats were incubated for 24h with gradient concentrations of Vaspin, and granulosa lutein cells incubated with 0.5% bovine serum albumin were used as controls. The proliferation, apoptosis, angiogenesis, progesterone (P4) and estradiol (E2) were detected by CCK-8, Anneixn-FITC/PI staining, angiogenesis experiment and ELISA. Western blot was applied to observe the expression levels of proteins related to cell proliferation, apoptosis, angiogenesis and MEK/MAPK signaling pathway. RESULTS: Compared with the Control group, Vaspin could significantly up-regulate the proliferation of granulosa lutein cells and reduce the apoptosis. Moreover, Vaspin promoted the angiogenesis of granulosa lutein cells and the production of P4 and E2 in a concentration-dependent manner. Furthermore, Vaspin up-regulated the CyclinD1, CyclinB1, Bcl2, VEGFA and FGF-2 expression in granulosa lutein cells, and down-regulated the level of Bax. Also, Vaspin increased the p-MEK1 and p-p38 levels. CONCLUSION: Vaspin can up-regulate the proliferation and steroidogenesis of rat luteal cells and reduce apoptosis, which may be related to the influence of MEK/MAPK activity.

Enantioselective Reductive Cross-Couplings of Olefins by Merging Electrochemistry with Nickel Catalysis.

The merger of electrochemistry and transition metal catalysis has emerged as a powerful tool to join two electrophiles in an enantioselective manner. However, the development of enantioselective electroreductive cross-couplings of olefins remains a challenge. Inspired by the advantages of the synergistic use of electrochemistry with nickel catalysis, we present here a Ni-catalyzed enantioselective electroreductive cross-coupling of acrylates with aryl halides and alkyl bromides, which affords chiral α-aryl carbonyls in good to excellent enantioselectivity. Additionally, this catalytic reaction can be applied to (hetero)aryl chlorides, which is difficult to achieve by other methods. The combination of cyclic voltammetry analysis with electrode potential studies suggests that the NiI species activates aryl halides by oxidative addition and alkyl bromides by single-electron transfer.

Microbial Dimethylsulfoniopropionate Cycling in Deep Sediment of the Mariana Trench.

Dimethylsulfoniopropionate (DMSP) and related organic sulfur compounds play key roles in global sulfur cycling. Bacteria have been found to be important DMSP producers in seawater and surface sediments of the aphotic Mariana Trench (MT). However, detailed bacterial DMSP cycling in the Mariana Trench subseafloor remains largely unknown. Here, the bacterial DMSP-cycling potential in a Mariana Trench sediment core (7.5 m in length) obtained at a 10,816-m water depth was investigated using culture-dependent and -independent methods. The DMSP content fluctuated along the sediment depth and reached the highest concentration at 15 to 18 cm below the seafloor (cmbsf). dsyB was the dominant known DMSP synthetic gene, existing in 0.36 to 1.19% of the bacteria, and was identified in the metagenome-assembled genomes (MAGs) of previously unknown bacterial DMSP synthetic groups such as Acidimicrobiia, Phycisphaerae, and Hydrogenedentia. dddP, dmdA, and dddX were the major DMSP catabolic genes. The DMSP catabolic activities of DddP and DddX retrieved from Anaerolineales MAGs were confirmed by heterologous expression, indicating that such anaerobic bacteria might participate in DMSP catabolism. Moreover, genes involved in methanethiol (MeSH) production from methylmercaptopropionate (MMPA) and dimethyl sulfide (DMS), MeSH oxidation, and DMS production were highly abundant, suggesting active conversions between different organic sulfur compounds. Finally, most culturable DMSP synthetic and catabolic isolates possessed no known DMSP synthetic and catabolic genes, and actinomycetes could be important groups involved in both DMSP synthesis and catabolism in Mariana Trench sediment. This study extends the current understanding of DMSP cycling in Mariana Trench sediment and highlights the need to uncover novel DMSP metabolic genes/pathways in extreme environments. IMPORTANCE Dimethylsulfoniopropionate (DMSP) is an abundant organosulfur molecule in the ocean and is the precursor for the climate-active volatile gas dimethyl sulfide. Previous studies focused mainly on bacterial DMSP cycling in seawater, coastal sediment, and surface trench sediment samples, but DMSP metabolism in the Mariana Trench (MT) subseafloor sediments remains unknown. Here, we describe the DMSP content and metabolic bacterial groups in the subseafloor of the MT sediment. We found that the tendency for vertical variation of the DMSP content in the MT was distinct from that of the continent shelf sediment. Although dsyB and dddP were the dominant DMSP synthetic and catabolic genes in the MT sediment, respectively, both metagenomic and culture methods revealed multiple previously unknown DMSP metabolic bacterial groups, especially anaerobic bacteria and actinomycetes. The active conversion of DMSP, DMS, and methanethiol may also occur in the MT sediments. These results provide novel insights for understanding DMSP cycling in the MT.

A Novel Azo-Linked Polymer Bearing Trifluoromethyl Groups for I2 Capture.

In this work, a novel three nitro-group-bearing monomer 3,6-dinitro-9-(2-trifluoromethyl-4-nitrophenyl)-carbazole (Car-3NO2 -CF3 ) via a CN coupling reaction between 3,6-dinitro-9H-carbazole (Car-2NO2 ) and 2-chloro-5-nitrobenzotrifluoride is synthesized, and obtained single crystal and single crystal analysis data for this compound. The crystal system of Car-3NO2 -CF3 is monoclinic and it has a P 21/c space group. This new monomer (Car-3NO2 -CF3 ) is also utilized to synthesize a novel azo-linked polymer (Azo-Car-CF3 ). The trifluoromethyl group has polar CF bonds, and thus it is an effective functional group for the capture of iodine. Azo-Car-CF3 has great thermal stability with a mass loss of only 10% at 414 °C, as well as good chemical stability as is demonstrated by its low solubility in common organic solvents such as tetrahydrofuran (THF), acetone, methanol, ethanol, and N,N-dimethylformamide (DMF). The specific surface area of Azo-Car-CF3 can reach as high as 335 m2  g-1 . Azo-Car-CF3 exhibits an excellent capacity for iodine adsorption and can reach up to 1198 mg g-1 in cyclohexane solution, and its adsorption capacity for iodine vapor can get to 2100 mg g-1 . In addition, ethanol can be used to trigger the release of the captured iodine to be easily released from Azo-Car-CF3 .

Medial meniscus posterior root tears and partial meniscectomy significantly increase stress in the knee joint during dynamic gait.

PURPOSE: As a simple and invasive treatment, arthroscopic medial meniscal posterior horn resections (MMPHRs) can relieve the obstructive symptoms of medial meniscus posterior root tears (MMPRTs) but with the risk of aggravating biomechanical changes of the joint. The aim of this study was to analyze dynamic simulation of the knee joint after medial meniscus posterior root tear and posterior horn resection. METHODS: This study established static and dynamic models of MMPRTs and MMPHRs on the basis of the intact medial meniscus model (IMM). In the finite element analysis, the three models were subjected to 1000 N axial static load and the human walking gait load defined by the ISO14243-1 standard to evaluate the influence of MMPRTs and MMPHRs on knee joint mechanics during static standing and dynamic walking. RESULTS: In the static state, the load ratio of the medial and lateral compartments remained nearly constant (2:1), while in the dynamic state, the load ratio varied with the gait cycle. After MMPHRs, at 30% of the gait cycle, compared with the MMPRTs condition, the maximum von Mises stress of the lateral meniscus (LM) and the lateral tibial cartilage (LTC) were increased by 166.0% and 50.0%, respectively, while they changed by less than 5% during static analysis. The maximum von Mises stress of the medial meniscus (MM) decreased by 55.7%, and that of the medial femoral cartilage (MFC) increased by 53.5%. CONCLUSION: After MMPHRs, compared with MMPRTs, there was no significant stress increase in articular cartilage in static analysis, but there was a stress increase and concentration in both medial and lateral compartments in dynamic analysis, which may aggravate joint degeneration. Therefore, in clinical treatments, restoring the natural structure of MMPRTs is first recommended, especially for physically active patients.

[The evolution of approach in the resuscitation of neonates born with meconium-stained amniotic fluid: a tale of two countries, China and U.S.A., in the past 60 years]. / 羊水胎粪污染新生儿复苏的前世今生：过去60年中美两国的演变史.

Neonates born through meconium-stained amniotic fluid (MSAF) may develop complications including meconium aspiration syndrome, persistent pulmonary hypertension of newborn and death. The approach to the resuscitation of these neonates has significantly evolved for the past few decades. Initially, under direct visualization technique, neonates with MSAF were commonly suctioned below the vocal cords soon after delivery. Since 2015, Neonatal Resuscitation Program (NRP®) of the American Academy of Pediatrics has recommended against "routine" endotracheal suctioning of non-vigorous neonates with MSAF but favored immediate resuscitation with positive pressure ventilation via face-mask bagging. However, the China neonatal resuscitation 2021 guidelines continue to recommend routine endotracheal suctioning of non-vigorous neonates born with MSAF at birth. This review article discusses the differences and the rationales in the approach in the resuscitation of neonates with MSAF between Chinese and American NRP® guidelines over the past 60 years.

Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial.

BACKGROUND: Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. METHODS: We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. RESULTS: CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. CONCLUSION: This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.

Cytokine release syndrome and relevant factors of CD19 targeted chimeric antigen receptor T cell therapy in relapsed/refractory B cell hematological malignancies.

OBJECTIVES AND METHODS: We reviewed the outcomes of 77 episodes of CD19 CAR-T therapy in 67 patients with B cell hematological malignancies from October 2016 to January 2020. Factors related to the grade of cytokine release syndrome (CRS) were explored by multivariate analysis, nonparametric test was conducted to explore the correlation between CRS and response. Kaplan-Meier curves were used to indicate survival profiles, and the correlation between CRS and survival was determined by the log-rank test. RESULTS: The rate of complete remission (CR) was 74.0% (57/77). CRS of any grade occurred in 68 of 77 episodes (grade 1: 32.5%, grade 2: 24.7%, grade 3: 22.1%, grade 4: 6.5%, grade 5: 2.6%). Patients with a history of transplantation had less severe CRS, and dose escalation-based infusion reduced the severity of CRS. Severe CRS was related to a higher CR rate but had no significant impact on event-free survival (EFS), relapse-free survival (RFS), or overall survival (OS). CONCLUSION: As a common adverse reaction of CAR-T therapy, the severity of CRS can be alleviated by dose escalation infusion, a history of transplantation was correlated with less severe CRS. Severe CRS was related to better response but was unrelated to long-term survival.

[Accuracy of prostatic ultrasonography versus MRI in measuring prostate volume].

OBJECTIVE: To compare the accuracy of different methods of measuring the prostate volume (PV) based on the manifestations of prostatic ultrasonography and MRI. METHODS: Using the drainage method, we measured the volumes of 101 prostatic specimens collected from radical prostatectomy. And with the measures obtained as reference standards, we calculated the PV of the patients with the maximum width (W), height (H) and length (L) of the prostates obtained preoperatively by transabdominal ultrasonography (TAUS), transrectal ultrasonography (TRUS) and MRI using the ellipsoidal formula (PV = W × H × L × 0.52), bullet formula (PV = W × H × L × 0.65) and 3D reconstruction technology. We evaluated the accuracy of the above methods using the Mann-Whitney U test, intraclass correlation coefficient (ICC), and Bland-Altman scatterplot. RESULTS: No statistically significant differences were observed between the specimen and preoperative PVs. The ICCs of the specimen PVs obtained by MRI 3D reconstruction, TRUS bullet formula, MRI ellipsoidal formula and TAUS ellipsoidal formula were 0.978, 0.862, 0.857 and 0.745, respectively. The Bland-Altman scatterplot exhibited that the preoperative PV calculated by MRI 3D reconstruction had the highest consistency with that of the specimen PV, followed by that measured by TRUS bullet formula and that obtained by MRI ellipsoidal formula, while that determined by TAUS ellipsoidal formula had a low consistency. CONCLUSION: The MRI 3D reconstruction technology is the most reliable method for the measurement of PV, followed by TRUS bullet formula, but the latter is recommended for its high applicability in clinical practice.

Developmental neurotoxicity and toxic mechanisms induced by olaquindox in zebrafish.

Olaquindox (OLA) has been widely used as an animal feed additive in China for decades; however, its toxicity and toxic mechanisms have not been well investigated. In this study, the developmental neurotoxicity and toxic mechanisms of OLA were evaluated in zebrafish. Zebrafish embryos were exposed to different concentrations of OLA (25-1,000 mg/L) from 6 to 120 hours post fertilization (hpf). OLA exposure resulted in many abnormal phenotypes in zebrafish, including shortened body length, notochord degeneration, spinal curvature, brain apoptosis, damage of axon and peripheral motor neuron, and hepatotoxicity. Interestingly, OLA increased zebrafish spontaneous tail coiling, while reduced locomotor capacity. Quantitative polymerase chain reaction (Q-PCR) showed that the expression levels of nine marker genes for nervous system functions or development, namely, α1-tubulin, glial fibrillary acidic protein (gfap), myelin basic protein (mbp), synapsinII a (syn2a), sonic hedgehog a (shha), encoding HuC (elavl3), mesencephalic astrocyte-derived neurotrophic factor (manf) growth associated protein 43 (gap43), and acetylcholinesterase (ache) were all down-regulated significantly in zebrafish after treated with OLA. Besides, the anti-apoptotic and pro-apoptotic genes bcl-2/bax ratio was reduced. These results show that OLA exposure could cause severe developmental neurotoxicity in the early stages of zebrafish life and OLA might induce neurotoxicity by inhibiting the expression of neuro-developmental genes and promoting apoptosis.

[Study on difference of effect of Huoxue drugs and Yiqi Huoxue drugs on tumor metastasis based on immune remodeling].

Tumor metastasis is an important cause of tumor treatment failure. Its molecular mechanism is closely related to tumor cells remodeling immune cells and immunosuppressive microenvironment, so as to create a suitable soil for tumor cell invasion and growth. "Huoxue Huayu" is one of the important therapeutic principles in cancer treatment, but the influence of Huoxue drugs on tumor metastasis has been controversial in clinical application. In this paper, we systematically summarized the comparative study of Huoxue drugs and Yiqi Huoxue drugs in tumor metastasis in recent years, and discussed the differences of molecular mechanisms of Huoxue drugs and Yiqi Huoxue drugs in anti-tumor metastasis from the perspective of immune remodeling, so as to provide scientific basis for clinical rational application of Huoxue drugs and Yiqi Huoxue drugs.

Sustained transmission of the ceftriaxone-resistant Neisseria gonorrhoeae FC428 clone in China.

BACKGROUND: Ceftriaxone resistance in Neisseria gonorrhoeae has become an imminent threat to effective control of gonorrhoea globally. In recent years, the ceftriaxone-resistant FC428 clone has shown international dissemination. After our first report of the FC428 clone in China in 2016, we now describe another six cases of FC428-related ceftriaxone-resistant N. gonorrhoeae isolates from 2017 and 2018. OBJECTIVES: To identify the phenotypic and molecular characteristics of newly reported ceftriaxone-resistant isolates in China and to investigate the relationship between these isolates and FC428 clones reported globally. METHODS: Antimicrobial susceptibility to ceftriaxone, cefixime, azithromycin, spectinomycin, penicillin, ciprofloxacin and tetracycline was determined by the agar dilution method. N. gonorrhoeae multi-antigen sequence typing (NG-MAST), MLST and N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) were performed for genotyping and SNPs extracted from whole-genome sequences were used for phylogenetic analysis. RESULTS: All isolates were resistant to ceftriaxone, cefixime, penicillin, tetracycline and ciprofloxacin, but were susceptible to azithromycin and spectinomycin. NG-MAST, MLST and NG-STAR genotyping showed that all isolates shared identical or similar STs (<10 bp difference) to FC428 (NG-MAST ST3435, MLST ST1903, NG-STAR ST233) and contained the same mosaic penA allele 60.001. Phylogenetic analysis showed the Chinese isolates spreading in the whole phylogenetic tree and fully mixed with other international isolates. Half of the Chinese isolates were more closely related (<100 SNPs) to Japanese isolates than other international isolates. CONCLUSIONS: The newly reported cases in China were related to the internationally spreading FC428 clone. These isolates might have played a central role in international transmission of the FC428 clone. High ceftriaxone doses (1-2 g) still provide effective therapy.

Multimodal imaging of spontaneous subretinal hemorrhage in a young male: a case report.

BACKGROUND: Spontaneous subretinal hemorrhage (SSRH) is a rare disease that severely affects the visual function, and is difficult to diagnose. This study aimed to describe the multimodality imaging characteristics of SSRH in a young male patient. CASE PRESENTATION: A 28-year-old male was presented to our hospital with "sudden drop of left eye vision for one week." Three weeks ago, he was admitted to other hospital due to sudden severe pain and unclear vision in the left eye for 1 h. The intraocular pressure was 69 mmHg, and the blood pressure was 230/120 mmHg. Skull CT and MRI detected abnormal signal shadows in the left eye and no abnormalities in the brain. B-ultrasonography indicated occupying lesions in the left eye. Two weeks later, the patient came to our hospital for treatment as the vision of the left eye had decreased sharply. Admission examination: blood pressure was 200/120 mmHg, best-corrected visual acuity was 20/20 in the right eye and hand motion in the left eye. Fundus details could not be evaluated in the left eye because of hemorrhage in the vitreous cavity. B-ultrasonography of the left eye revealed a dense, diffuse intravitreal hemorrhage. Skull MRI showed an abnormal signal shadow in the left eyeball, suggesting intraocular hemorrhage. Vitrectomy revealed a dome-shaped lesion in the peripheral part of the inferotemporal region during the operation. Postoperative indocyanine green angiography (ICGA) of the lesion showed hypofluorescence and no leakage or altered morphology during the whole imaging process. Follow-up showed gradual reabsorption of SSRH. CONCLUSIONS: In this case, SSRH was considered to be associated with high blood pressure. Multimodal imaging provides accurate data for the diagnosis and follow-up of the disease.

The Effect of Cognitive Impairment on the Prognosis of Major Depressive Disorder.

The study recruited 168 patients diagnosed with major depressive disorder (MDD). The nine-item Patient Health Questionnaire (PHQ-9) and Perceived Deficits Questionnaire for Depression (PDQ-D) were lower and the Digit Symbol Substitution Test (DSST) was higher in the community volunteers than those in MDD patients. Depression-related scores (17-item Hamilton Depression Rating Scale [HAMD-17], Clinical Global Impressions-Severity of Illness Scale [CGI-S], and PHQ-9), functioning-related scores (Sheehan Disability Scale [SDS]), and Work Efficiency and Activity Damage-Specific Health Problems questionnaire work productivity loss were decreased, and the quality of life-related scores (European Quality of life-5 Dimensions [EQ-5D] utility score) were increased in the MDD patients. PDQ-D was decreased and DSST was increased with the increase of follow-up time. Linear regression indicated that cognitive symptoms (PDQ-D and DSST) improved more slowly than depressive symptoms (PHQ-9). At baseline, PDQ-D was related with functioning (SDS and work productivity loss). PDQ-D and DSST were related with EQ-5D utility score. In addition, at month 6, PDQ-D was related with functioning (SDS and work productivity loss) and EQ-5D utility score. Cognitive impairment might be a risk for MDD and MDD-related changes in the functioning and quality of life.

[Recognition and discussion of several technical details in neonatal resuscitation training].

In the current revision of neonatal resuscitation training course material and its in-depth learning, referring to the American original textbook on neonatal resuscitation, the authors have some recognition and discussion about its several technical details or translated words. These include the location and time period of postnatal rapid assessment, the expression of respiratory questions, the pressing position in the tracheal intubation, and the expression of respiratory questions in the flow chart of resuscitation, etc. The accurate understanding and interpretation of the above will help grass-roots training to be carried out more accurately and effectively.

Identification of Internationally Disseminated Ceftriaxone-Resistant Neisseria gonorrhoeae Strain FC428, China.

In 2016, we identified a ceftriaxone-resistant Neisseria gonorrhoeae isolate in China. The strain genotype was identical to the resistant clone FC428 that originated in Japan. Enhanced international collaborative surveillance programs are crucial to track the transmission of the ceftriaxone-resistant clones.

Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein.

Pyrotinib is a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor that is used to treat HER2-positive breast cancer. In this study we investigated the metabolism and disposition of pyrotinib in six healthy Chinese men after a single oral dose of 402 mg of [14C]pyrotinib. At 240 h postdose, the mean cumulative excretion of the dose radioactivity was 92.6%, including 1.7% in urine and 90.9% in feces. In feces, oxidative metabolites were detected as major drug-related materials and the primary metabolic pathways were O-depicoline (M1), oxidation of pyrrolidine (M5), and oxidation of pyridine (M6-1, M6-2, M6-3, and M6-4). In plasma, the major circulating entities identified were pyrotinib, SHR150980 (M1), SHR151468 (M2), and SHR151136 (M5), accounting for 10.9%, 1.9%, 1.0%, and 3.0%, respectively, of the total plasma radioactivity based on the AUC0-∞ ratios. Approximately 58.3% of the total plasma radioactivity AUC0-∞ was attributed to covalently bound materials. After incubation of human plasma with [14C]pyrotinib at 37 °C for 2, 5, 8, and 24 h, the recovery of radioactivity by extraction was 97.4%, 91.8%, 69.6%, and 46.7%, respectively, revealing covalent binding occurred independently of enzymes. A group of pyrotinib adducts, including pyrotinib-lysine and pyrotinib adducts of the peptides Gly-Lys, Lys-Ala, Gly-Lys-Ala, and Lys-Ala-Ser, was identified after HCl hydrolysis of the incubated plasma. Therefore, the amino acid residue Lys190 of human serum albumin was proposed to covalently bind to pyrotinib via Michael addition. Finally, the covalently bound pyrotinib could dissociate from the human plasma protein and be metabolized by oxidation and excreted via feces.

Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: A retrospective study of national surveillance data from 2013 to 2016.

BACKGROUND: Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China. METHODS AND FINDINGS: In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC ≥ 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC ≥ 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%-19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%-2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual. CONCLUSIONS: To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China.

Transcriptomic analysis of immune-related genes in the lipopolysaccharide-stimulated hepatopancreas of the mudflat crab Helice tientsinensis.

The mudflat crab Helice tientsinensis is one of the most economically important aquaculture species in China. Nevertheless, it is susceptible to various diseases caused by viruses, bacteria and rickettsia-like organisms. A better understanding of the immune system and genes related to the responses to bacterial and viral infection is required. Herein, the hepatopancreas transcriptome of H. tientsinensis was analyzed by comparing control and lipopolysaccharide (LPS)-stimulated RNA-Seq data, yielding 91,885,038 bp and 13.78 Gb of clean reads. Following assembly and annotation, 93,207 unigenes with an average length of 883 bp were identified, of which 31,674 and 13,700 were annotated in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively. Following LPS, 4845 differentially expressed genes (DEGs) were identified, of which 2491 and 2354 were up- and down-regulated, respectively. To further investigate immune-related DEGs, KEGG enrichment analysis identified immune response pathways, most notably the peroxisome and Toll-like receptor signaling pathways. Quantitative real time-PCR (qRT-PCR) confirmed the up-regulation of a random selection of DEGs. This systematic transcriptomic analysis of the innate immune pathway in H. tientsinensis expands our understanding of the immune system in crabs.