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Abstract Background Cancer‐related pain is one of the common priority symptoms in advanced lung cancer patients at the end‐of‐life (EOL). Alleviating pain is undoubtedly a critical component of palliative care in lung cancer. Our study was initiated to examined trends in opioid prescription‐level outcomes as potential indicators of undertreated pain in China. Methods This study used data on 1330 patients diagnosed with lung cancer of urban city medical insurance in China who died between 2014 and 2017. Opioid prescription‐level outcomes were determined by annual trends of the proportion of patients filling an opioid prescription, the total dose of opioids filled by decedents, and morphine milligram equivalents per day (MMED) at the EOL (defined as the 60 days before death). We further analyzed monthly changes in the number of opioid prescriptions filled, MMED, and mean daily dose of opioids per prescription (MDDP) of the last 60 days of life by year at death and age, respectively. Results A total of 959 patients with exact dates of death were included, with 432 cases (45.06%; 95% CI: 44.36%–45.77%) receiving at least one opioid prescription at the EOL. The declining trends were shown in the proportion of patients filling any opioid prescription, the total dose of opioids filled by decedents and MMED, with an annual decrease of 0.341% (p = 0.01), 104.23 mg (p = 0.011) and 2.84 mg (p = 0.014), respectively. Within the 31–60 days to the 0–30 days of life, the MMED declined 6.08 mg (95% CI: −7.14 to −5.03; p = 0.000351), while the number of opioid prescriptions rose 0.66 (95% CI: 0.160–1.16; p = 0.025). Like the MMED, the MDDP fell 4.11 mg (95% CI: −5.86 to −2.37; p = 0.005) within the last month before death compared to the previous month. Conclusion Terminal lung cancer populations in urban China have experienced reduced access to opioids at the EOL. The clinicians did not prescribe a satisfactory dose of opioids per prescription, while the patients suffered increasing pain in the last 30 days of life. Sufficient opioid analgesic administration should be advocated for lung cancer patients during the EOL period.

Abstract There remains an unmet need for targeted therapies against advanced non‐small‐cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti‐HER2 agent, this prospective, single‐arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti‐HER2 antibody inetetamab and pan‐HER TKI pyrotinib in HER2‐posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose‐escalation part, 240 mg, 320 mg; dose‐expansion part, 320 mg). Primary endpoints were dose‐limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose‐escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment‐related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4–8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2‐mutant NSCLC.

Abstract EGFR exon 20 insertion (20ins)-positive non-small-cell lung cancer (NSCLC) is an uncommon disease with limited therapeutic options and dismal prognosis. Here we report the activity, tolerability, potential mechanisms of response and resistance for dual targeting EGFR 20ins with JMT101 (anti-EGFR monoclonal antibody) plus osimertinib from preclinical models and an open label, multi-center phase 1b trial (NCT04448379). Primary endpoint of the trial is tolerability. Secondary endpoints include objective response rate, duration of response, disease control rate, progression free survival, overall survival, the pharmacokinetic profile of JMT101, occurrence of anti-drug antibodies and correlation between biomarkers and clinical outcomes. A total of 121 patients are enrolled to receive JMT101 plus osimertinib 160 mg. The most common adverse events are rash (76.9%) and diarrhea (63.6%). The confirmed objective response rate is 36.4%. Median progression-free survival is 8.2 months. Median duration of response is unreached. Subgroup analyses were performed by clinicopathological features and prior treatments. In patients with platinum-refractory diseases (n = 53), confirmed objective response rate is 34.0%, median progression-free survival is 9.2 months and median duration of response is 13.3 months. Responses are observed in distinct 20ins variants and intracranial lesions. Intracranial disease control rate is 87.5%. Confirmed intracranial objective response rate is 25%.

ObjectiveAquaporin-4 (AQP4) antibody-seropositive optic neuritis (AQP4-ON) is one of the most common types of optic neuritis in China. However, the association between AQP4-ON and vision-related quality of life (QoL) and depression remains poorly understood.MethodsIn this cross-sectional study, 57 patients with optic neuritis were evaluated for their vision-related QoL using a Chinese version of the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) and assessed for depressive symptoms using a Chinese version of the Beck Depression Inventory-II (BDI-II). Data regarding participants’ age, sex, visual acuity, and the number of recurrence events were gathered. Linear regression analysis was employed to investigate the relationships between AQP4-ON and vision-related QoL, as well as depression.ResultsOf the 57 included patients, 28 were AQP4-ON, and 29 were idiopathic optic neuritis (ION). AQP4-ON demonstrated a significant correlation with a decreased VFQ-25 composite score (Mean difference, −11.65 [95% CI, −21.61 to −1.69]; p = 0.023) and an increased BDI-II score (Mean difference, 6.48 [95% CI, 0.25 to 12.71]; p = 0.042) when compared to ION. The BDI-II score was correlated with the VFQ-25 composite score (Spearman ρ = −0.469; p

Abstract Recent reports have demonstrated that Sox9+HNF4α+ hepatocytes are involved in liver regeneration after chronic liver injury; however, little is known about the origin of Sox9+HNF4α+ hepatocytes and the regulatory mechanism. Employing a combination of chimeric lineage tracing, immunofluorescence, and immunohistochemistry, we demonstrate that Sox9+HNF4α+ hepatocytes, generated by transition from mature hepatocytes, play an important role in the initial phase after partial hepatectomy (PHx). Additionally, knocking down the expression of Sox9 suppresses hepatocyte proliferation and blocks the recovery of lost hepatic tissue. In vitro and in vivo assays demonstrated that Bcl3, activated by LPS, promotes hepatocyte conversion and liver regeneration. Mechanistically, Bcl3 forms a complex with and deubiquitinates YAP1 and further induces YAP1 to translocate into the nucleus, resulting in Sox9 upregulation and mature hepatocyte conversion. We demonstrate that Bcl3 promotes Sox9+HNF4α+ hepatocytes to participate in liver regeneration, and might therefore be a potential target for enhancing regeneration after liver injury.

Abstract Background Liver cancer is one of the most common malignancies in the world with a poor prognosis. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80–90% of cases. The initiation and progression of HCC are closely associated with chronic liver inflammation. In addition, HCC is often accompanied by cell senescence. Senescent hepatocytes can secrete various inflammatory factors, collectively called the senescence-associated secretory phenotype (SASP). The SASP has been confirmed to promote the occurrence of liver cancer by affecting the inflammatory microenvironment. However, its role and the underlying mechanism of hepatic SASP in hepatocarcinogenesis are not clearly understood. Therefore, a better understanding of the pathogenic mechanisms of the effect of the hepatic SASP on the occurrence of HCC is still needed. Methods The study aims to explore the role of SASP factors and the underlying mechanism in tumorigenesis and the progression of HCC in vivo. We used diethylnitrosamine (DEN) combined with carbon tetrachloride (CCl4) (DEN-CCl4) to establish liver cancer model in wild-type (WT) mice and Bcl3 knockout (Bcl3 −/− ) mice. β-galactosidase (β-gal) staining was performed to evaluate the degree of cellular senescence. Immunohistochemistry (IHC) were used to detect the degree of cellular senescence and the activation of macrophage. PCR chip and clinical tissue chip assays were used to estimate the RNA levels of SASP factors and NF-κB related genes, and their protein levels were examined by Western blot assays. Results DEN-CCl4 induced cellular senescence in mouse hepatocytes. In addition, senescent hepatocytes might release a variety of inflammatory factors that further activate macrophages, thereby changing the microenvironmental state and promoting the occurrence of HCC. Mechanistically, the NF-κB pathway is important because it regulates the SASP. Therefore, we used a PCR chip to detect the expression of NF-κB-related genes in senescent liver tissue. Our results showed that the expression of Bcl3 was increased in senescent hepatocytes, and knocking out Bcl3 significantly inhibited the secretion of hepatocyte SASP factors and the activation of macrophages, thereby inhibiting hepatocarcinogenesis. Finally, in clinical tissues adjacent to HCC tissues in patients, the expression of Bcl3 and IL-8 correlated with poor prognosis in HCC patients. Conclusion The hepatic SASP can further induce the activation of macrophages during hepatocarcinogenesis, thereby promoting the occurrence of HCC, and that this process is closely related to the expression of Bcl3 in hepatocytes.

Bacterial lipoproteins perform a diverse array of functions including bacterial envelope biogenesis and microbe-host interactions. Lipoproteins in gram-negative bacteria are sorted to the outer membrane (OM) via the localization of lipoproteins (Lol) export pathway. The ATP-binding cassette (ABC) transporter LolCDE initiates the Lol pathway by selectively extracting and transporting lipoproteins for trafficking. Here, we report cryo-EM structures of LolCDE in apo, lipoprotein-bound, and AMPPNP-bound states at a resolution of 3.5 to 4.2 Å. Structure-based disulfide crosslinking, photo-crosslinking, and functional complementation assay verify the apo-state structure and reveal the molecular details regarding substrate selectivity and substrate entry route. Our studies snapshot 3 functional states of LolCDE in a transport cycle, providing deep insights into the mechanisms that underlie LolCDE-mediated lipoprotein sorting in E. coli.

Abstract Background The liver possesses a powerful regeneration ability, which is correlated with the stemness of hepatocytes in the portal vein (PV). However, the mechanism underlying the maintenance of hepatocyte stemness has not been elucidated. Here, we hypothesized that high levels of lipopolysaccharide from the portal vein might maintain the stemness of hepatocytes in the PV area. Methods First, we examined the location of hepatic stem cells and the concentration of lipopolysaccharide (LPS) in the portal vein and inferior vena cava. Then, we assessed the effect of LPS on stemness maintenance in mice by using antibiotics to eliminate LPS and knocking out the LPS receptor, TLR4. In vitro, the effect of LPS on the stemness of hepatocytes was investigated by colony and sphere formation assays and assessment of pluripotent and stem cell marker expression. Furthermore, we studied the mechanism by which LPS regulates the stemness of hepatocytes. Finally, we ligated the portal vein branch to further verify the effect of LPS. Results We found that a high level of LPS from the portal vein was correlated with the location of hepatic stem cells in the PV area, and elimination of LPS by antibiotics inhibited the expression of the stemness marker. LPS promoted colony and sphere formation and induced the upregulation of pluripotent and stem cell markers in AML12 cells. Furthermore, in the reprogramming medium, LPS facilitated the dedifferentiation of mature hepatocytes into hepatic progenitor-like cells, which exhibited a bipotent differentiation capacity in vivo and in vitro. Mechanistically, LPS bound TLR4 to regulate stemness of hepatocytes via the activation of YAP1 signaling, and blockade of YAP1 abolished the LPS-induced cell stemness and upregulation of pluripotent markers. Conclusions Our study implies a correlation between LPS/TLR4/YAP1 signaling and cell stemness, and LPS was shown to be involved in stemness maintenance of hepatocytes in the PV area. LPS might be used to induce the dedifferentiation of mature hepatocytes into progenitor-like cells for repair of liver injury.

BackgroundDeafness-dystonia-optic neuronopathy (DDON) syndrome, a condition that predominantly affects males, is caused by mutations in translocase of mitochondrial inner membrane 8A (TIMM8A)/deafness dystonia protein 1 (DDP1) gene and characterized by progressive deafness coupled with other neurological abnormalities. In a previous study, we demonstrated the phenotype of male mice carrying the hemizygous mutation of Timm8a1-I23fs49X. In a follow-up to that study, this study aimed to observe the behavioral changes in the female mutant (MUT) mice with homologous mutation of Timm8a1 and to elucidate the underlying mechanism for the behavioral changes.Materials and methodsHistological analysis, transmission electron microscopy (EM), Western blotting, hearing measurement by auditory brainstem response (ABR), and behavioral observation were compared between the MUT mice and wild-type (WT) littermates.ResultsThe weight of the female MUT mice was less than that of the WT mice. Among MUT mice, both male and female mice showed hearing impairment, anxiety-like behavior by the elevated plus maze test, and cognitive deficit by the Morris water maze test. Furthermore, the female MUT mice exhibited coordination problems in the balance beam test. Although the general neuronal loss was not found in the hippocampus of the MUT genotype, EM assessment indicated that the mitochondrial size showing as aspect ratio and form factor in the hippocampus of the MUT strain was significantly reduced compared to that in the WT genotype. More importantly, this phenomenon was correlated with the upregulation of translation of mitochondrial fission process protein 1(Mtfp1)/mitochondrial 18 kDa protein (Mtp18), a key fission factor that is a positive regulator of mitochondrial fission and mitochondrial size. Interestingly, significant reductions in the size of the uterus and ovaries were noted in the female MUT mice, which contributed to significantly lower fertility in the MUT mice.ConclusionTogether, a homologous mutation in the Timm8a1 gene caused the hearing impairment and psychiatric behavioral changes in the MUT mice; the latter phenotype might be related to a reduction in mitochondrial size regulated by MTP18.

Pleurotus citrinopileatus, a golden oyster mushroom, is popular in Asia and has pharmacological functions. However, the effects of polysaccharide-peptides extracted from Pleurotus citrinopileatus and underlying mechanism on digestive systme have not yet been clarified. Here, we determined the composition of two polysaccharide-peptides (PSI and PSII) from P. citrinopileatus and investigated the protective effects of on hepatoprotective and gut microbiota. The results showed that PSI and PSII were made up of similar monosaccharide moieties, except for the varying ratios. Furthermore, PSI and PSII showed that they have the hepatoprotective effects and significantly increased the viabilities and cellular total superoxide dismutase activities increased significantly in HepG2 cells. Intracellular triglyceride content and extracellular alanine aminotransferase and aspartate transaminase contents markedly decreased following treatment with 40 and 50 μg/mL PSI and PSII, respectively. Moreover, PSI and PSII activated the adiponectin pathway and reduced lipid accumulation in liver cells. PSI and PSII elevated short-chain fatty acid concentrations, especially butyric and acetic acids. 16S rRNA gene sequencing analysis showed that PSI promoted the relative abundances of Bifidobacteria, Lactobacillus, Faecalibacterium, as well as Prevotella generas in the gut. PSII markedly suppressed the relative abundances of Escherichia-Shigella and Bacteroides generas. We speculate that the PSI and PSII play a role through liver-gut axis system. Polysaccharide-peptides metabolize by gut microbiota to produce short-chain fatty acids (SCFAs) and in turn influence liver functions.

Background and PurposeAn increasing number of autoimmune encephalitis (AE)-associated autoantibodies have been successfully characterized. However, many cases of AE remain unexplained on account of unknown antibodies. The aim of the present study was to identify a novel antibody against collapsin response mediator protein 2 (CRMP2) in suspected AE patients.MethodsA patient’s serum and cerebrospinal fluid samples tested negative for known AE antibodies; however, strong immunolabel signals were observed in the neuronal cytoplasm of the cortex, hippocampus, and Purkinje cells on rat brain sections. Immunoprecipitation from the rat brain protein lysate, followed by mass spectrometry analysis, was used to identify the targeting antigen. Western blotting and cell-based assay with antigen-overexpressing HEK293T cells were used for antibody specificity, epitope, IgG subtype determination, and retrospective study.ResultsAn antibody against CRMP2, a synaptic protein involved in axon guidance, was identified. The immunostains of the patient’s samples on rat brain sections were eliminated by pre-absorption with HEK293T cells overexpressing CRMP2. The samples specifically immunoreacted with CRMP2, but not with CRMP1, CRMP3, CRMP4, and CRMP5. The C-terminus of CRMP2 with 536 amino acids contained the epitope for antibody binding. The subtype analysis showed that the anti-CRMP2 antibody was IgG4. Furthermore, a screening of 46 patients with neurological disoders and neuro-cytoplasm immunostainings on rat brain sections resulted in the identification of anti-CRMP2 antibodies in a case of encephalomyelitis. The two patients responded well to immunotherapies.ConclusionsThis study discovered that a novel anti-CRMP2 antibody was associated with suspected AE and thus should be included in the testing list for AE.

Objectives Osimertinib has exhibited promising central nervous system (CNS) efficacy in Epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) patients. In real-world clinical practice, patients would turn to plasma genotyping or take osimertinib blindly after CNS progression on previous tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib in those patients according to their T790M mutational status has not been explored. Materials and methods Twenty-five patients who received osimertinib due to intracranial progressions with stable extracranial diseases after early-generation EGFR-TKI treatment were collected from 1032 EGFR-mutated NSCLC. Plasma samples were analyzed for EGFR mutations using next-generation sequencing (NGS) or polymerase chain reaction (PCR). Results Among the 25 patients, 17 patients took plasma genotyping before osimertinib treatment with 8 patients EGFR T790M mutation-positive and the rest started osimertinib blindly. The median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.12-9.94) and median intracranial PFS (iPFS) was 14.4 months (95% CI: 7.27-21.59) for the total population. No statistical difference was found in PFS and iPFS among patients with different EGFR T790M mutational statuses. Intracranial disease control rate (DCR) was 100.0% for 14 patients with evaluable intracranial lesions despite different T790M mutational statuses. DCR for extracranial lesions and overall lesions were 100.0%, 66.7%, and 87.5% for patients with T790M, no T790M, and unknown T790M mutational status, respectively. Conclusion For EGFR-mutated NSCLC patients with only intracranial progressions after previous TKI treatments, osimertinib is a promising treatment option regardless of T790M mutational status from plasma genotyping.

Abstract Background There is a gap between China and developed countries in Europe and America as to the normalization of cardiac magnetic resonance (CMR) diagnostic reports. The aim of this study was to construct a structured CMR report template suitable for China's actual conditions. Methods Cardiac magnetic resonance standardized image interpretation and post‐processing guidelines and CMR report guidelines are the consensus and recommendations of the Society for Cardiovascular Magnetic Resonance (SCMR) experts whose goal is to ensure the consistent quality and repeatability of CMR reports. This structured CMR report template was constructed based on the guidelines for standardized image interpretation, post processing and reporting of CMR examinations, combined with the experiences learned in Germany and the practical experiences in China. It consisted of three parts: Device and Methods, Findings (Structure and function, Tissue Characterization), Summary and Conclusion. Detailed directions were provided section by section. Results This structured CMR report template underlined the comprehensive analysis of the results of morphological, functional and tissue characteristics to provide conclusive opinions and answer the corresponding important questions raised by the clinicians. Conclusion The standardization of qualitative and quantitative assessments of CMR results is the core of structured reporting of CMR.

Vector reduction is a very common operation to reduce a vector into a single scalar value in many scientific and engineering application scenarios. Therefore a fast and efficient vector reduction circuit has great significance to the real-time system applications. Usually the pipeline structure is widely adopted to increase the throughput of the vector reduction circuit and achieve maximum efficiency. In this paper, to deal with multiple vectors of variable length in random input sequence, a novel tag based fully pipelined vector reduction circuit is firstly proposed, in which a cache state module is used to queer and update the cache state of each vector. However, when the quantity of the input vector becomes large, a larger cache state module is required, which consumes more combinational logic and lower the operating frequency. To solve this problem, a high speed circuit is proposed in which the input vectors will be divided into several groups and sent into the dedicated cache state circuits, which can improve the operating frequency. Compared with other existing work, the prototype circuit and the improved circuit based on the prototype circuit can achieve the smallest Slices × us (

Accumulated hard tissue debris (AHTD) is an inevitable by-product during endodontic treatment and is difficult to remove completely using traditional syringe and needle irrigation (SNI). Adjunctive irrigation is proposed to assist the clean-up of AHTD. This systematic review and meta-analysis aimed to evaluate the AHTD removal efficacy of different root canal irrigation devices using micro-computed tomography (Micro-CT). A literature search was carried out within the main scientific databases until 20 June 2022. All results were screened with detailed eligibility criteria. Eleven studies were included for analysis. SNI, passive ultrasonic irrigation (PUI), negative pressure systems, sonically activated irrigation (SAI), mechanical-activated system and laser-activated irrigation (LAI) were assessed. PUI is superior to SNI for debris removal and LAI has better AHTD removal performance than PUI. The negative pressure system and mechanical-activated system were proved to be less effective. Registration: PROSPERO (CRD42021273892).

In this study, different reaction-bonded boron carbide (RBBC) composites with a free carbon addition from 0 to 15 wt% were prepared, and the effect of the carbon content on the mechanical properties was discussed. With the free carbon addition increase from 0 to 15 wt%, the residual silicon content in the RBBC composite decreased first and then increased. Meanwhile, the strength of the RBBC composite improved first and then worsened. In the RBBC composite without free carbon, the B4C grains are obviously dissolved, the grains become facet-shape, and the grain boundary becomes straight. The microstructure of the composite was tested by SEM, and the phase composition of the composite was tested by XRD. The RBBC composite with the addition of 10 wt% free carbon has the highest flexural strength (444 MPa) and elastic modulus (329 GPa). In the composite with a 10 wt% carbon addition, the phase distribution is uniform and the structure is compact.

Immune checkpoint inhibitors (ICIs) have come to play an increasingly prominent role in the treatment of lung cancer, and some are recommended as a first-line treatment for late-stage non-small-cell lung cancer, either as a monotherapy or in combination with chemotherapy. Accordingly, the indications of Food and Drug Administration-approved ICIs have increased. In this background, China has implemented various policies to encourage and accelerate the marketing of domestic and imported innovative antitumor drugs. Eight ICIs have been approved in China. Among these, four imported programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have received approval for six indications, and one domestic PD-1 inhibitor has received approval for one indication for lung cancer in 2018. Numerous clinical trials of ICIs for lung cancer are underway in China. This review aims to summarize the recent advances and future directions of ICIs, including PD-1 inhibitors, PD-L1 inhibitors, cytotoxic T lymphocyte-associated antigen-4 inhibitors, bi-specific antibodies, and a novel inhibitor of T-cell immune-receptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains in immunotherapies for lung cancer in China.

Reaction-bonded silicon carbide (RBSC) has become an important structural ceramic with the benefit of being capable of preparing complex-shaped products. In order to fabricate high-performance RBSC, particle gradation of raw SiC combined with slip casting was used to prepare the porous preform before liquid silicon infiltration (LSI). The microstructural and mechanical properties of RBSC were compared by adding different amounts of carbon black (CB) content from 4 wt% to 10 wt%. Two pore structures with submicron and nano pores formed in the preform. As the amounts of carbon black increased, the mechanical properties improved and then suddenly weakened due to residual silicon initiating a nonuniform microstructure. The elastic modulus of the preform with 8 wt%CB after LSI was 389 ± 4 GPa and the flexural strength was 340 ± 17 MPa, which improved by about 150% compared to other rapid prototyping methods and has attractive application prospects.

Abstract Background Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations. Methods Tumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib. Results EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0–12.9 months; range 4.9–14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented. Conclusions This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

Curli play critical roles in biofilm formation, host cell adhesion, and colonization of inert surfaces in many Enterobacteriaceae. In Escherichia coli, curli biogenesis requires 7 curli-specific gene (csg) products-CsgA through G-working in concert. Of them, CsgG and CsgF are 2 outer membrane (OM)-localized components that consists of the core apparatus for secretion and assembly of curli structural subunits, CsgB and CsgA. Here, we report the cryogenic electron microscopy (cryo-EM) structure of CsgG in complex with CsgF from E. coli. The structure reveals that CsgF forms a stable complex with CsgG via a 1:1 stoichiometry by lining the upper lumen of the nonameric CsgG channel via its N-terminal 27 residues, forming a funnel-like entity plugged in the CsgG channel and creating a unique secretion channel with 2 constriction regions, consistent with the recently reported structure of the CsgG-CsgF complex. Functional studies indicate that export of CsgF to the cell surface requires the CsgG channel, and CsgF not only functions as an adaptor that bridges CsgB with CsgG but also may play important roles in controlling the rates of translocation and/or polymerization for curli structural subunits. Importantly, we found that a series of CsgF-derived peptides are able to efficiently inhibit curli production to E. coli when administrated exogenously, highlighting a potential strategy to interfere biofilm formation in E. coli strains.

Recently, topic models such as Latent Dirichlet Allocation (LDA) have been widely used in large-scale web mining. Many large-scale LDA training systems have been developed, which usually prefer a customized design from top to bottom with sophisticated synchronization support. We propose an LDA training system named ZenLDA, which follows a generalized design for the distributed data-parallel platform. The novelty of ZenLDA consists of three main aspects: (1) it converts the commonly used serial Collapsed Gibbs Sampling (CGS) inference algorithm to a Monte-Carlo Collapsed Bayesian (MCCB) estimation method, which is embarrassingly parallel; (2) it decomposes the LDA inference formula into parts that can be sampled more efficiently to reduce computation complexity; (3) it proposes a distributed LDA training framework, which represents the corpus as a directed graph with the parameters annotated as corresponding vertices and implements ZenLDA and other well-known inference methods based on Spark. Experimental results indicate that MCCB converges with accuracy similar to that of CGS, while running much faster. On top of MCCB, the ZenLDA formula decomposition achieved the fastest speed among other well-known inference methods. ZenLDA also showed good scalability when dealing with large-scale topic models on the data-parallel platform. Overall, ZenLDA could achieve comparable and even better computing performance with state-of-the-art dedicated systems.

Boron carbide (B4C) ceramics were synthesized by spark plasma sintering at a temperature between 1600 and 2050 °C without employing any sintering additives. The effect of sintering process parameters, such as temperature, holding time, pressure, hearting rate, and pulsed electric current, and the particle size of the raw powder on the densification behavior and mechanical properties of B4C ceramics, were comprehensively and systematically investigated. Hardness and fracture toughness of B4C that has a density close to the theoretical value were found to be 33.5 ± 0.2 GPa and 3.21 ± 0.13 MPa·m1/2, respectively. Electron backscatter diffraction (EBSD) analysis revealed no abnormal growth of grains due to an increase in holding time and pressure. Twin structures present in ceramics are beneficial for their mechanical performance.

Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction between multiple susceptibility genes, environmental factors and the immune system. Over 40 T1D susceptibility regions have been suggested by recent genome-wide association studies; however, the specific genes and their role in the disease remain elusive. The objective of this study is to identify the susceptibility gene(s) in the 12q13 region and investigate the functional link to the disease pathogenesis. A total of 19 SNPs in the 12q13 region were analyzed by the TaqMan assay for 1,434 T1D patients and 1,865 controls. Thirteen of the SNPs are associated with T1D (best p = 4x10(-11)), thus providing confirmatory evidence for at least one susceptibility gene in this region. To identify candidate genes, expression of six genes in the region was analyzed by real-time RT-PCR for PBMCs from 192 T1D patients and 192 controls. SNP genotypes in the 12q13 region are the main factors that determine ERBB3 mRNA levels in PBMCs. The protective genotypes for T1D are associated with higher ERBB3 mRNA level (p