Results of the phase IIa study to evaluate the efficacy and safety of rezivertinib (BPI-7711) for the first-line treatment of locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation from a phase I/IIa study.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This phase IIa study was part of a phase I/IIa study (NCT03386955), aimed to evaluate the efficacy and safety of rezivertinib as the first-line treatment for patients with locally advanced or metastatic/recurrent EGFR mutated non-small cell lung cancer (NSCLC). METHODS: Patients received the first-line treatment of 180 mg rezivertinib orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: From Jun 12, 2019, to Oct 17, 2019, 43 patients were enrolled. At the data cutoff date on Dec 23, 2021, the ORR by BICR was 83.7% (95% CI: 69.3-93.2%). The median DoR was 19.3 (95% CI: 15.8-25.0) months. The median PFS by BICR was 20.7 (95% CI: 13.8-24.8) months and 22.0 (95% CI: 16.8-26.3) months by investigators. Data on OS was immature. Totally, 40 (93.0%) patients had at least one treatment-related adverse event while 4 (9.3%) of them were grade ≥ 3. CONCLUSIONS: Rezivertinib (BPI-7711) showed promising efficacy and a favorable safety profile for the treatment among the locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation in the first-line setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03386955.

A prognostic model using the neutrophil-albumin ratio and PG-SGA to predict overall survival in advanced palliative lung cancer.

OBJECTIVE: Inflammation and malnutrition are common in patients with advanced lung cancer undergoing palliative care, and their survival time is limited. In this study, we created a prognostic model using the Inflam-Nutri score to predict the survival of these patients. METHODS: A retrospective cohort study was conducted on 223 patients with advanced, histologically confirmed unresectable lung cancer treated between January 2017 and December 2018. The cutoff values of the neutrophil-albumin ratio (NAR) and Patient-Generated Subjective Global Assessment (PG-SGA) score were determined by the X-tile program. Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analysis were performed to identify prognostic factors of overall survival (OS). We then established a nomogram model. The model was assessed by a validation cohort of 72 patients treated between January 2019 and December 2019. The predictive accuracy and discriminative ability were assessed by the concordance index (C-index), a plot of the calibration curve and risk group stratification. The clinical usefulness of the nomogram was measured by decision curve analysis (DCA). RESULTS: The nomogram incorporated stage, supportive care treatment, the NAR and the PG-SGA score. The calibration curve presented good performance in the validation cohorts. The model showed discriminability with a C-index of 0.76 in the training cohort and 0.77 in the validation cohort. DCA demonstrated that the nomogram provided a higher net benefit across a wide, reasonable range of threshold probabilities for predicting OS. The survival curves of different risk groups were clearly separated. CONCLUSIONS: The NAR and PG-SGA scores were independently related to survival. Our prognostic model based on the Inflam-Nutri score could provide prognostic information for advanced palliative lung cancer patients and physicians.

Cloning and Characterization of a Cold-adapted Chitosanase from Marine Bacterium Bacillus sp. BY01.

Chitosanase plays an important role in the production of chitooligosaccharides (CHOS), which possess various biological activities. Herein, a glycoside hydrolase (GH) family 46 chitosanase-encoding gene, csnB, was cloned from marine bacterium Bacillus sp. BY01 and heterologously expressed in Escherichia coli. The recombinant chitosanase, CsnB, was optimally active at 35 °C and pH 5.0. It was also revealed to be a cold-adapted enzyme, maintaining 39.5% and 40.4% of its maximum activity at 0 and 10 °C, respectively. Meanwhile, CsnB showed wide pH-stability within the range of pH 3.0 to 7.0. Then, an improved reaction condition was built to enhance its thermostability with a final glycerol volume concentration of 20%. Moreover, CsnB was determined to be an endo-type chitosanase, yielding chitosan disaccharides and trisaccharides as the main products. Overall, CsnB provides a new choice for enzymatic CHOS production.

Notch signaling regulates the expression of glycolysis-related genes in a context-dependent manner during embryonic development.

Glycolysis, the classic pathway for producing energy, has been known to be involved in neural development. Notch signaling also contributes to neural development and regulation of glycolysis in various tissues. However, the role of Notch signaling in glycolysis-related gene regulation during neural development is poorly understood. Here, we analyzed mRNA expression patterns and levels of glucose transporters (GLUT) as well as rate-limiting enzymes in glycolysis using zebrafish mib1ta52b mutants, in which Notch signaling was deficient at the early embryonic and larval stages. Our results indicated that in neural tissues, Notch signaling positively regulates glut1a and glut3a expression and negatively regulates hk2 expression at the larval stage but may not regulate them during early embryonic stages. Therefore, these results suggest that Notch signaling regulates glycolysis-related gene expression in a context-dependent manner in neural tissues at different developmental stages.

[Effect of Raw Materials and Preparing Process on the Composition of Lime-Ash].

As the saying goes that "no ash, no glaze", lime-ash has been the core material widely used to prepare glaze in ancient China. Among all the lime-ashes, those made in Jingdezhen are the most influential and representative ones. Not only did lime-ash contribute greatly to the prosperity of porcelain making of Jingdezhen in Song, Yuan, Ming and Qing Dynasty, but also it has a complicated, rigorous and a touch of "mysterious" in its preparation process, technical principle and glaze mechanism. Therefore, the research of the lime-ash has been an important subject in exploring the "secret" of ancient Chinese porcelain production by Chinese and foreign researchers. In this paper, four representative firewood and two lime stones as the raw materials were collected for the comparative studies, and three kinds of lime-ash with different smolder times were collected from one of the only two traditional lime-ash workshops in Shou'an town nearby Jingdezhen urban area. The chemical composition and phase composition of the raw materials and lime-ash with different smolder times made in Jingdezhen were discussed by testing with the Energy Dispersive X Ray Fluorescence (EDXRF) and X-Ray Diffraction (XRD). The results showed that Fe(2)O(3), MnO contents reaches 1.41% and 1.52% respectively, but the P(2)O(5) content is just 0.54% of Langqi grass which is lower than other firewood that is not only benefited to form the characteristic of "Green in the white" in Jingdezhen traditional glaze, but also is favor to enhance the transparency of glaze and promote the coloration of traditional under-glazed color painted porcelain, such as the blue and white porcelain. The CaO content of grey lime stone is lower than that of the black lime stone with MgO content of 35.79%.This could be the main reason why the craftsmen prefer to use black lime stone to prepare lime-ash. In addition, the EDXRF results show that the K(2)O, P(2)O(5), MnO and Fe(2)O(3) contents have increased as the time of smoldering increases. In the meanwhile, the calcium carbonate (CaCO(3)) phase has also increased, but the calcium hydroxide (Ca(OH)(2)) phase has decreased. The study helps Jingdezhen porcelain "look like jade" and is also good to avoid the "thickness" of glaze when there is a certain amount of Ca(OH)(2) in glaze. So it could be concluded that the unique raw materials and smolder technology of the lime-ash which have provided the technical support for the development of lime-ash glaze are the unique features of ancient Jingdezhen ash glaze.

Knowledge, attitudes, and current practices toward lung cancer palliative care management in China: a national survey.

Scope: The present investigation seeks to illuminate the current state and disparities in the knowledge, attitudes, and practices (KAP) among healthcare professionals regarding the management of lung cancer palliative care (LCPC) in China, while simultaneously assessing the prevalence and context of patient-controlled analgesia (PCA) usage in the management of cancer-related pain. Methods: A total of 2093 healthcare practitioners from 706 hospitals across China completed a structured questionnaire that probed various facets of LCPC management. The questionnaire consisted of seven thematic sections, incorporating chi-square tests and Fisher's exact probabilities to statistically assess the discrepancies in KAP among healthcare professionals across different hospital grades. Ordered data distributions among hospital grades were compared using non-parametric Kruskal-Wallis H and Mann-Whitney U tests. Multiple-choice items were subjected to multiple-response cross-tabulation analysis, while the Spearman rank-order correlation coefficient was employed to gauge potential associations among variables. Results: Around 84.2% of the respondents perceived anti-tumor therapy to be of equal importance to palliative care. Statistically significant differences (χ² = 27.402, P = 0.002) in satisfaction levels were observed, with participants from Tertiary hospitals demonstrating higher satisfaction compared to those from Secondary and Primary hospitals. Pain emerged as the most prevalent symptom necessitating LCPC. Major impediments to LCPC adoption included patients' and families' concerns about the safety of long-term palliative care-related drug use. 31.1% of the respondents cited the most frequent rationale for PCA use as cases involving patients who required systemic administration of large opioid doses or exhibited intolerable adverse reactions to opioids. The principal deterrents against the use of PCA for cancer pain management were (1): apprehension about adverse drug reactions due to overdose (2), concern about the potential for opioid addiction, and (3) the anticipated increase in patients' economic burdens. Over the preceding 24-month period, 33.9% of the surveyed healthcare practitioners reported no engagement in either online or offline LCPC-related training initiatives. Conclusion: This study emphasizes the pressing need for comprehensive training in LCPC among Chinese health personnels, particularly focusing on the effective management of cancer pain symptoms.

Hypoxic microenvironment promotes dermal fibroblast migration and proliferation via a BNIP3-autophagy pathway.

Upon injury, nearby cells, including fibroblasts at the wound edge, are often found in a hypoxic microenvironment. Nevertheless, the influence of hypoxia on skin fibroblasts is poorly understood. Using previously established mouse full-thickness wounds, we show that Bcl-2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3) expression was significantly elevated at the wound edge, and hypoxia treatment enhanced BNIP3 expression in fibroblasts. Interestingly, BNIP3 promoted the migration and proliferation, as well as the activation of autophagy, in fibroblasts under hypoxia. The hypoxia-induced autophagy was found to induce the migration and proliferation of fibroblasts, a process that could be reversed by knocking down the autophagy-related gene for autophagy protein 5, ATG5. Furthermore, hypoxia-inducible factor 1 subunit alpha (HIF-1α) was significantly upregulated in fibroblasts under hypoxia treatment, and HIF-1α knockdown attenuated the hypoxia-induced expression of BNIP3 and the migration and proliferation of fibroblasts. Altogether, our results establish the hypoxia-BNIP3-autophagy signaling axis as a newly identified regulatory mechanism of skin fibroblast migration and proliferation upon wounding. Autophagy intervening might thus represent a promising therapeutic strategy for patients with chronic refractory wounds.

JK5G postbiotics attenuate immune-related adverse events in NSCLC patients by regulating gut microbiota: a randomized controlled trial in China.

Scope: This study aimed to evaluate the effects of JK5G postbiotics to regulate imbalanced gut microbiota and its impacts on the efficacy and incidence rate of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Methods: This randomized, double-blind, placebo-controlled trial was conducted in China and included non-squamous or squamous NSCLC patients without EGFR, ROS1, and ALK alteration, treatment-naive, and stage IIIb-IV. Patients were randomly (1:1) divided into two groups to receive four cycles (three weeks for each cycle) of programmed cell death-1 (PD-1) plus chemotherapy plus placebo (control group, n = 30) or to receive PD-1 plus chemotherapy plus JK5G postbiotics (JK5G group, n = 30). The primary endpoint was objective response rate. The secondary endpoints were quality of life (QoL), adverse effects, and the 16S DNA sequencing of gut microbiota, blood inflammatory cytokines, and lymphocyte subsets. This study was registered at www.chictr.org.cn (ChiCTR2200064690). Results: Sixty patients were enrolled. The objective response rate was 36.67% (11/30) in the control group and 50.00% (15/30) in the JK5G group (p = 0.297). The JK5G group had better QoL and nutritional levels, as well as lower depression symptoms than the control group (all p < 0.05). Moreover, the JK5G group had a lower incidence of anemia (63.33% vs. 13.33%, p < 0.001), decreased lymphocyte count (20.00% vs. 0%, p = 0.010), decreased appetite (53.33% vs. 16.67%, p = 0.003), nausea (33.33% vs. 6.67%, p = 0.010), and asthenia (30.00% vs. 6.67%, p = 0.017) than the control group. Moreover, JK5G attenuated gut microbiota imbalance, accompanied by increased Faecalibacterium, Ruminococcaceae, and fecal butyrate concentration, and diminished Escherichia-Shigella. Furthermore, JK5G administration significantly decreased the levels of pro-inflammatory markers, including TNF-α, IL-2, and C-reactive protein (CRP) (all p < 0.05). Significant increases in CD3+CD4+ T cells and CD4/CD8 ratio were observed in the peripheral blood of JK5G group patients (all p < 0.05). The enterotype data showed that patients were clustered into Blautia (E1) and Escherichia-Shigella (E2) enterotypes, and JK5G postbiotics intervention might be related to enterotype modulations. Conclusion: Our current findings indicated that JK5G postbiotics might attenuate irAEs, and enhance the QoL and nutrition levels of advanced NSCLC patients who received ICIs. JK5G postbiotics could also improve the gut microbiota structures and ameliorate the tumor microenvironment and inflammation. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2200064690.

Combined early palliative care for non-small-cell lung cancer patients: a randomized controlled trial in Chongqing, China.

Purpose: More effective approaches are needed to improve the prognosis of non-small-cell lung cancer (NSCLC) patients. Thus, we used the E-warm model to assess how early integration of interdisciplinary palliative care was related to the quality of life (QoL), psychological functioning, pain management, and nutrition factors of NSCLC patients. Methods: This randomized controlled trial enrolled 280 newly diagnosed NSCLC patients, which were randomly divided (1:1) into combined early palliative care (CEPC) and standard oncological care (SC) groups. At baseline and after 24 weeks, the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale, Hospital Anxiety and Depression Scale (HADS), and the Patient Health Questionnaire-9 (PHQ-9) were used to assess QoL and psychological function, respectively. The Numerical Rating Scale (NRS) and Patient-Generated Subjective Global Assessment (PG-SGA) were used to assess cancer patients' pain and nutrition levels. The primary outcome was overall survival (OS). Secondary outcomes comprised changes in the QoL, psychological functioning, pain, and nutrition state. The intention-to-treat method was applied for analysis. This study was registered at www.chictr.org.cn (ChiCTR2200062617). Results: Of the 140 patients enrolled in the CEPC and SC groups, 102 and 82 completed the research. The CEPC group presented higher QoL than the SC group (p < 0.05). Additionally, fewer patients presented depressive symptoms in the CEPC group than in the SC group (p < 0.05), as well as better nutritional status (p = 0.007) and pain management (p = 0.003). Compared to the SC group, CEPC patients had significantly longer OS (20.4 vs. 24.6 months, p = 0.042; HR: 0.19; 95% CI: 0.04-0.85, p = 0.029). Conclusion: With combined early palliative care, NSCLC patients lived longer, had better QoL, were psychologically stable, were in less pain, and were more nutritionally satisfied.

Multi-valent mRNA vaccines against monkeypox enveloped or mature viron surface antigens demonstrate robust immune response and neutralizing activity.

Monkeypox was declared a global health emergency by the World Health Organization, and as of March 2023, 86,000 confirmed cases and 111 deaths across 110 countries have been reported. Its causal agent, monkeypox virus (MPV) belongs to a large family of double-stranded DNA viruses, Orthopoxviridae, that also includes vaccinia virus (VACV) and others. MPV produces two distinct forms of viral particles during its replication cycles: the enveloped viron (EV) that is released via exocytosis, and the mature viron (MV) that is discharged through lysis of host cells. This study was designed to develop multi-valent mRNA vaccines against monkeypox EV and MV surface proteins, and examine their efficacy and mechanism of action. Four mRNA vaccines were produced with different combinations of surface proteins from EV (A35R and B6R), MV (A29L, E8L, H3L and M1R), or EV and MV, and were administered in Balb/c mice to assess their immunogenicity potentials. A dynamic immune response was observed as soon as seven days after initial immunization, while a strong IgG response to all immunogens was detected with ELISA after two vaccinations. The higher number of immunogens contributed to a more robust total IgG response and correlating neutralizing activity against VACV, indicating the additive potential of each immunogen in generating immune response and nullifying VACV infection. Further, the mRNA vaccines elicited an antigen-specific CD4+ T cell response that is biased towards Th1. The mRNA vaccines with different combinations of EV and MV surface antigens protected a mouse model from a lethal dose VACV challenge, with the EV and MV antigens-combined vaccine offering the strongest protection. These findings provide insight into the protective mechanism of multi-valent mRNA vaccines against MPV, and also the foundation for further development of effective and safe mRNA vaccines for enhanced protection against monkeypox virus outbreak.

Comparison of the performance of the GLIM criteria, PG-SGA and mPG-SGA in diagnosing malnutrition and predicting survival among lung cancer patients: A multicenter study.

BACKGROUND & AIMS: The present study aimed to compare the ability of the GLIM criteria, PG-SGA and mPG-SGA to diagnose malnutrition and predict survival among Chinese lung cancer (LC) patients. METHODS: This was a secondary analysis of a multicenter, prospective, nationwide cohort study, 6697 LC inpatients were enrolled between July 2013 and June 2020. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and quadratic weighted Kappa coefficients were calculated to compare the ability to diagnose malnutrition. There were 754 patients who underwent follow-up for a median duration of 4.5 years. The associations between the nutritional status and survival were analyzed by the Kaplan-Meier method and multivariable Cox proportional hazard regression models. RESULTS: The median age of LC patients was 60 (53, 66), and 4456 (66.5%) were male. There were 617 (9.2%), 752 (11.2%), 1866 (27.9%), and 3462 (51.7%) patients with clinical stage Ⅰ, Ⅱ, Ⅲ, and Ⅳ LC, respectively. Malnutrition was present in 36.1%-54.2% (as evaluated using different tools). Compared with the PG-SGA (used as the diagnostic reference), the sensitivity of the mPG-SGA and GLIM was 93.7% and 48.3%; the specificity was 99.8% and 78.4%; and the AUC was 0.989 and 0.633 (P < 0.001). The weighted Kappa coefficients were 0.41 for the PG-SGA vs. GLIM, 0.44 for the mPG-SGA vs. GLIM, and 0.94 for the mPG-SGA vs PG-SGA in patients with stage Ⅰ-Ⅱ LC. These values were respectively 0.38, 0.39, and 0.93 in patients with stage Ⅲ-Ⅳ of LC. In a multivariable Cox analysis, the mPG-SGA (HR = 1.661, 95%CI = 1.348-2.046, P < 0.001), PG-SGA (HR = 1.701, 95%CI = 1.379-2.097, P < 0.001) and GLIM (HR = 1.657, 95%CI = 1.347-2.038, P < 0.001) showed similar death hazard ratios. CONCLUSIONS: The mPG-SGA provides nearly equivalent power to predict the survival of LC patients as the PG-SGA and the GLIM, indicating that all three tools are applicable for LC patients. The mPG-SGA has the potential to be an alternative replacement for quick nutritional assessment among LC patients.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. METHODS: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. RESULTS: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. CONCLUSIONS: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.

Isolation, Biosynthesis, and Biological Activity of Polycyclic Xanthones From Actinomycetes.

Natural products from actinomycetes serve as a crucial source of clinical pharmaceuticals, especially antibiotics and anticancer agents. Among them, polycyclic xanthones belong to a growing group of highly oxygenated aromatic polyketides with a xanthone-containing angular hexacyclic framework. These biosynthetically unique small molecules are of great interest due to their wide spectrum of biological activities, especially the remarkable antibacterial activity against gram-positive bacteria and the significant antineoplastic effects toward various cancer cells at nanomolar concentrations. Their complex structures and significant bioactivities have aroused considerable attention in the chemical and biological communities in recent decades. This review covers the isolation, the biosynthesis, and the biological studies toward these structurally complex and biologically active molecules.

Early Palliative Care in Patients With Non-Small-Cell Lung Cancer: A Randomized Controlled Trial in Southwest China.

PURPOSE: Effective interventions to improve prognosis in non-small-cell lung cancer (NSCLC) are urgently needed. We assessed the effect of the early integration of interdisciplinary palliative care (based on WARM model) for patients with NSCLC on the quality of life (QoL), psychological state, cancer pain and nutritional status. METHODS: In this randomized controlled trial, 120 newly diagnosed NSCLC patients were enrolled and randomly assigned (1:1) to the combined early palliative care (CEPC) group integrated with standard oncologic care or standard oncological care (SC) group. QoL and psychological state were assessed at baseline and at 24 weeks by Functional Assessment of Cancer Therapy-Lung (FACT-L) scale, the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire-9 (PHQ-9), respectively. Cancer nutritional and pain status were assessed with the use of the Patient-Generated Subjective Global Assessment (PG-SGA) and Numerical Rating Scale (NRS), respectively. The primary outcome was the change in the quality of life, psychological state and nutritional status at 24 weeks. Analysis was by intention to treat. RESULTS: 120 patients were enrolled: 60 in CEPC group (38 completed) and 60 in the SC group (32 completed). CEPC group had a better QoL than SC group (P < .05). In addition, fewer patients in the CEPC group than in the SC group had depressive (P = .005) symptoms. Furthermore, patients in CEPC group had a better nutritional status than SC group (P = .001). CONCLUSION: Among patients with non-small-cell lung cancer, early palliative care led to significant improvements in quality of life, psychological state and nutritional status.

Altered brain functional activity and connectivity in bone metastasis pain of lung cancer patients: A preliminary resting-state fMRI study.

Bone metastasis pain (BMP) is one of the most prevalent symptoms among cancer survivors. The present study aims to explore the brain functional activity and connectivity patterns in BMP of lung cancer patients preliminarily. Thirty BMP patients and 33 healthy controls (HCs) matched for age and sex were recruited from inpatients and communities, respectively. All participants underwent fMRI data acquisition and pain assessment. Low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were applied to evaluate brain functional activity. Then, functional connectivity (FC) was calculated for the ALFF- and ReHo-identified seed brain regions. A two-sample t-test or Manny-Whitney U-test was applied to compare demographic and neuropsychological data as well as the neuroimaging indices according to the data distribution. A correlation analysis was conducted to explore the potential relationships between neuroimaging indices and pain intensity. Receiver operating characteristic curve analysis was applied to assess the classification performance of neuroimaging indices in discriminating individual subjects between the BMP patients and HCs. No significant intergroup differences in demographic and neuropsychological data were noted. BMP patients showed reduced ALFF and ReHo largely in the prefrontal cortex and increased ReHo in the bilateral thalamus and left fusiform gyrus. The lower FC was found within the prefrontal cortex. No significant correlation between the neuroimaging indices and pain intensity was observed. The neuroimaging indices showed satisfactory classification performance between the BMP patients and HCs, and the combined ALFF and ReHo showed a better accuracy rate (93.7%) than individual indices. In conclusion, altered brain functional activity and connectivity in the prefrontal cortex, fusiform gyrus, and thalamus may be associated with the neuropathology of BMP and may represent a potential biomarker for classifying BMP patients and healthy controls.

Safety, Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients With Advanced NSCLC With EGFR T790M Mutation: A Phase 1 Dose-Escalation and Dose-Expansion Study.

INTRODUCTION: Rezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M mutations. This study was designed to evaluate the safety, efficacy, and pharmacokinetics of rezivertinib for patients having advanced NSCLC with EGFR T790M mutation. METHODS: This phase 1 study (NCT03386955) was conducted across 20 sites in the People's Republic of China. Patients received rezivertinib at six oral dose levels (30 mg, 60 mg, 120 mg, 180 mg, 240 mg, 300 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were safety for the dose-escalation phase and objective response rate by the blinded independent central review for the total study population. RESULTS: A total of 19 patients in dose-escalation phase using the standard 3 + 3 design principle and 153 patients in dose-expansion phase were enrolled from September 11, 2017, to August 23, 2019. The data cutoff date was on June 15, 2020. No dose-limiting toxicity occurred in the dose-escalation phase. The treatment-related adverse events were observed in 82.0% (141 of 172) of patients, and 17.4% (30 of 172) had grade greater than or equal to 3, among which decreased neutrophil count (2.9%), leukopenia (2.9%), and pneumonia (2.9%) were the most common. The overall blinded independent central review-evaluated objective response rate was 59.3% (102 of 172, 95% confidence interval: 51.6-66.7), and the median progression-free survival was 9.7 (95% confidence interval: 8.3-11.1) months. CONCLUSIONS: Rezivertinib was found to have promising efficacy with a manageable safety profile in patients with EGFR T790M-mutated advanced NSCLC. Further study is warranted.

Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study.

INTRODUCTION: Rezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC. METHODS: Patients with locally advanced or metastatic/recurrent NSCLC with confirmed EGFR T790M mutation who progressed after first-/second-generation EGFR TKI therapy or primary EGFR T790M mutation were enrolled. Patients received rezivertinib at 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, and safety. This study is registered with Clinical Trials.gov (NCT03812809). RESULTS: A total of 226 patients were enrolled from July 5, 2019, to January 22, 2020. By the data cutoff date on January 24, 2022, the median duration of follow-up was 23.3 months (95% confidence interval [CI]: 22.8-24.0). The ORR by blinded independent central review was 64.6% (95% CI: 58.0%-70.8%), and DCR was 89.8% (95% CI: 85.1%-93.4%). The median duration of response was 12.5 months (95% CI: 10.0-13.9), and median PFS was 12.2 months (95% CI: 9.6-13.9). The median overall survival was 23.9 months (95% CI: 20.0-not calculated [NC]). Among 91 (40.3%) patients with central nervous system (CNS) metastases, the median CNS PFS was 16.6 months (95% CI: 11.1-NC). In 29 patients with more than or equal to one brain target lesion at baseline, the CNS ORR and CNS DCR were 69.0% (95% CI: 49.2%-84.7%) and 100% (95% CI: 88.1%-100%), respectively. Time to progression of CNS was 16.5 months (95% CI: 9.7-NC). Of 226 patients, 188 (83.2%) had at least one treatment-related adverse event, whereas grade more than or equal to 3 occurred in 45 (19.9%) patients. No interstitial lung disease was reported. CONCLUSIONS: Rezivertinib was found to have promising efficacy and favorable safety profile for patients with locally advanced or metastatic/recurrent NSCLC with EGFR T790M mutation.

Knockdown of SNORA47 Inhibits the Tumorigenesis of NSCLC via Mediation of PI3K/Akt Signaling Pathway.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a frequently diagnosed aggressive cancer all over the world. Small nucleolar RNAs (snoRNAs) are a group of non-coding mediatory RNAs. A previous report indicated that small nucleolar RNA 47 (SNORA47) is upregulated in NSCLC. However, the role of SNORA47 in NSCLC is unclear. MATERIAL AND METHODS: Cell proliferation was measured by immunofluorescence staining. Cell apoptosis and cycle of NSCLC were tested by flow cytometry and the protein expressions were investigated by Western-blot. Meanwhile, cell migration and invasion were detected by transwell assay. Xenograft mice model was established to detect the effect of SNORA47 knockdown on tumor growth of NSLC in vivo. RESULTS: Knockdown of SNORA47 significantly inhibited the proliferation of NSCLC cells via inducing cell apoptosis. Moreover, migration and invasion of NSCLC cells were notably decreased by SNORA47 shRNA. SNORA47 knockdown significantly induced G1 arrest in NSCLC cells via regulation of p27 Kip1, CDK2, and cyclin D1. Meanwhile, SNORA47 shRNA inhibited EMT process and PI3K/Akt signaling in NSCLC cells. Finally, silencing of SNORA47 significantly inhibited the tumor growth of NSCLC in vivo. CONCLUSION: Knockdown of SNORA47 significantly inhibited the tumorigenesis of NSCLC via inhibition of PI3K/Akt signaling and EMT process. Thereby, our finding might shed a new light on exploring the strategies for the treatment of NSCLC.

Evaluation of Dexamethasone-Induced Osteoporosis In Vivo Using Zebrafish Scales.

Glucocorticoid-induced osteoporosis (GIOP) is a major cause of secondary osteoporosis, and the pathogenic mechanisms of GIOP remain to be elucidated. Here, we show a rapid dexamethasone-induced osteoporosis animal model using zebrafish scales. Intraperitoneal injection of dexamethasone over a 5-day period suppressed the regeneration of scales. Furthermore, the circularity of the newly formed regenerated scales was also slightly reduced compared to that of the control group on day 5. The changes in bone-related enzymes, such as cathepsin K, tartrate-resistant acid phosphatase (TRAP) for bone resorption, and alkaline phosphatase (ALP) for bone formation, provide insight into the progression of bone diseases; therefore, we further developed a method to measure the activities of cathepsin K, TRAP, and ALP using zebrafish scales. We found that a lysis buffer with detergent at neutral pH under sonication efficiently helped extract these three enzymes with high activity levels. Interestingly, treatment with a dexamethasone injection produced considerably higher levels of cathepsin K activity and a lower Ca/P ratio than those in the control group, suggesting that dexamethasone increased osteoclast activity, with no significant changes in the activities of TRAP and ALP. Our GIOP model and enzyme assay method could help to design better treatments for GIOP.

Body Mass Index and Primary Headache: A Hospital-Based Study in China.

OBJECTIVE: Primary headache and obesity are highly prevalent disorders in the general population. Although many studies have reported an association between the two, there is still no overall comprehension about this relationship. To gain a more accurate understanding in this regard, we analyzed data from a 2011 cross-sectional study in Chongqing, China. METHODS: Patients with a chief complaint of headache were administered a headache questionnaire and diagnosed by neurology doctors in accordance with the International Classification of Headache Disorders 2nd Edition (ICHD-II) criteria. Patients aged < 18 years or diagnosed with secondary headache were excluded. RESULTS: Of 1327 patients who cited headache as the chief complaint, 16 were excluded for missing data, while 396 were diagnosed with chronic headache (177 chronic migraine [CM], 186 chronic tension-type headache [CTTH], and 33 other chronic headache) and 915 with episodic headache (369 episodic migraine [EM], 319 episodic tension-type headache [ETTH], and 227 other episodic headache). Chronic headache patients had a higher number of headache days per month, longer duration of headache history, and greater tendency to overuse analgesics than episodic headache patients. The CM and ETTH patients were more apt to be overweight and had a significantly greater body mass index (BMI; p < 0.05) than the EM and CTTH patients. Overweight (odds ratio [OR] = 3.64; 95% confidence interval (CI), 1.19-8.81) and obesity (OR = 28.63; 95% CI, 2.96-276.6) were independently associated with CM but not with other headaches, and this association was not influenced by other factors such as medication overuse. CONCLUSIONS: The relationship between headache and overweight/obesity varies depending on the type of primary headache. CM patients are more likely to have a higher body mass index than EM patients, while ETTH patients are more likely to be overweight/obese than CTTH patients.