Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices. Further improvement of potency and pharmacokinetics produced in vivo proof-of-concept tool molecule 20 (AM-1488), which reversed tactile allodynia in a mouse spared-nerve injury (SNI) model. Additional structural optimization provided highly potent potentiator 32 (AM-3607), which was cocrystallized with human GlyRα3 to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs).

Reading is an important high-level cognitive function of the human brain, requiring interaction among multiple brain regions. Revealing differences between children's large-scale functional brain networks for reading tasks and those of adults helps us to understand how the functional network changes over reading development. Here we used functional magnetic resonance imaging data of 17 adults (19-28 years old) and 16 children (11-13 years old), and graph theoretical analyses to investigate age-related changes in large-scale functional networks during rhyming and meaning judgment tasks on pairs of visually presented Chinese characters. We found that: (1) adults had stronger inter-regional connectivity and nodal degree in occipital regions, while children had stronger inter-regional connectivity in temporal regions, suggesting that adults rely more on visual orthographic processing whereas children rely more on auditory phonological processing during reading. (2) Only adults showed between-task differences in inter-regional connectivity and nodal degree, whereas children showed no task differences, suggesting the topological organization of adults' reading network is more specialized. (3) Children showed greater inter-regional connectivity and nodal degree than adults in multiple subcortical regions; the hubs in children were more distributed in subcortical regions while the hubs in adults were more distributed in cortical regions. These findings suggest that reading development is manifested by a shift from reliance on subcortical to cortical regions. Taken together, our study suggests that Chinese reading development is supported by developmental changes in brain connectivity properties, and some of these changes may be domain-general while others may be specific to the reading domain.

In this study, we tried to explore if xeroderma pigmentosum complementation group-A (XPA) expression is likely a prognostic prediction factor for locally advanced nasopharyngeal carcinoma (NPC) patients treated with platinum-based chemoradiotherapy, which was considered to bring chemotherapy-related severe toxicity compared with radiotherapy alone. Firstly, MTT assay revealed that downregulating XPA expression in NPC HONE1 and CNE1 cells decreased IC50 of cisplatin and sensitized cells to cisplatin. XPA expression was detected by immunohistochemistry in cancer tissues from locally advanced NPC patients treated with platinum-based chemoradiotherapy. The relationships between XPA expression and clinicopathologic features, overall survival and progression-free survival of patients were evaluated. The results showed that XPA expression was not associated with clinicopathologic parameters, but was likely an independent prognostic factor for patient survival. High XPA level predicts a poor prognosis, and the prediction values were higher in subgroups of younger, higher EBV antibody titer, or treated with concurrent chemoradiotherapy. Combining XPA levels and T/N classifications, we successfully classified these patients into low, medium and high risk groups for platinum-based chemoradiotherapy. These findings suggest that XPA levels may be a potential predictor of prognosis in locally advanced NPC patients treated with platinum-based chemoradiotherapy, and helpful for selecting patients likely to need and benefit from this treatment in future.

No abstract

Approximately 240 million people worldwide are chronically infected with hepatitis B virus (HBV), which represents a significant challenge to public health. The current goal in treating chronic HBV infection is to block progression of HBV-related liver injury and inflammation to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma, because we are unable to eliminate chronic HBV infection. Available therapies for chronic HBV infection mainly include nucleos/tide analogues (NAs), non-NAs, and immunomodulatory agents. However, none of them is able to clear chronic HBV infection. Thus, a new generation of anti-HBV drugs is urgently needed. Progress has been made in the development and testing of new therapeutics against chronic HBV infection. This review aims to summarize the state of the art in new HBV drug research and development and to forecast research and development trends and directions in the near future.

Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T‐cell–mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p‐AKT/p‐ERK/p‐MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol‐treated mice. The expression of GzmB/IFN‐γ/T‐bet in the CD8+ T‐cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol‐treated surgical specimens, the expression of p‐ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T‐cell population was significantly increased in propranolol‐treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p‐AKT/p‐ERK/p‐MEK in mouse tumor models, while inhibiting the expression of p‐ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.

Jejunal diverticulosis is uncommon and often asymptomatic. It can produce significant complications, and some complications are potentially life threatening and require early surgical treatment, such as obstruction, hemorrhage and perforation. There is no consensus on the management of this disease. Only a few cases of jejunal diverticulosis with midgut volvulus have been reported. We herein report a case of 57-year-old woman with jejunal diverticulosis causing small bowel volvulus who complained of intermittent upper abdominal pin-prick for 5 years that eventually progressed to a complete obstruction. The computed tomography scans revealed a mesenteric vessel "whirlpool" and laparotomy showed midgut volvulus secondary to jejunal diverticula. This case highlights jejunal diverticulosis causing small bowel volvulus as an uncommon mechanism of small bowel obstruction, which should be included in the differential diagnosis of small bowel obstruction.

The aim of this paper was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of nemonoxacin, a novel nonfluorinated quinolone, against Streptococcus pneumoniae in vitro. A modified infection model was used to simulate the pharmacokinetics of nemonoxacin following scaling of single oral doses and multiple oral dosing. Four S. pneumoniae strains with different penicillin sensitivities were selected, and the drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid maximum-effect (E max ) model was used to analyze the relationship between PK/PD parameters and drug effect. Analysis indicated that the killing pattern of nemonoxacin shows a dualism which is mainly concentration dependent when the MIC is low and that the better PK/PD index should be the area under the concentration-time curve for the free, unbound fraction of the drug divided by the MIC (fAUC 0 -24 /MIC), which means that giving the total daily amount of drug as one dose is appropriate under those conditions. When the MIC is high, the time (T) dependency is important and the valid PK/PD index should be the cumulative percentage of a 24-h period in which the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f%T>MIC), which means that to split the maximum daily dose into several separate doses will benefit the eradication of the bacteria. To obtain a 3-log 10 -unit decrease, the target values of fAUC 0 -24 /MIC and f%T>MIC are 47.05 and 53.4%, respectively. N emonoxacin, a novel nonfluorinated quinolone, exerts broad antibacterial activity by interrupting DNA synthesis in prokaryotic organisms (1). The antimicrobial spectrum includes Gram-positive and Gram-negative bacteria as well as atypical pathogens such as penicillin-resistant Streptococcus pneumoniae and methicillin-and vancomycin-resistant Staphylococcus aureus (2, 3). The antibacterial activity of nemonoxacin is stronger than that of levofloxacin and moxifloxacin against most Gram-positive cocci (4).Completed phase I clinical trials in China have demonstrated that nemonoxacin is well tolerated within the dose range of 125 to 1,000 mg and shows linear pharmacokinetics. The absorption peak appeared at 1 to 2 h, and the elimination half-life was 10 to 12 h (5). In a phase II clinical trial, the effect of nemonoxacin (500 or 750 mg daily for 7 to 10 days) was similar to that of 500 mg levofloxacin for treating community-acquired pneumonia (CAP) in adults (6). A phase III clinical trial has just completed. However, few studies have investigated the killing pattern and pharmacokinetic/pharmacodynamic (PK/PD) characteristics of this drug, which are needed for the dose regimen design.Compared to animal models, the PK process of the drug in humans could be well simulated in the in vitro models without considering species differences between human and animals (7, 8). Meanwhile, in vitro models allow determination of time-kill behavior and identification and optimization of PK/PD indices and breakpoints (9). In the present work, we...