BACKGROUND:This study evaluated biomarker profiles associated with therapeutic response and prognosis in resectable non-small cell lung cancer (NSCLC) receiving neoadjuvant camrelizumab plus chemotherapy. METHODS:In this single-arm phase II trial, patients with resectable stage IIIA-IIIB NSCLC received three cycles of camrelizumab plus chemotherapy, followed by surgery. Primary endpoints were pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), disease-free survival (DFS), and safety. Exploratory analyses assessed immune subsets in the tumor microenvironment (TME) and peripheral blood, cytokine profiles, circulating tumor DNA (ctDNA) dynamics, and spatial immune-tumor interactions. RESULTS:Thirty patients were enrolled (22 squamous, 8 adenocarcinoma); 27 underwent radical resection. The pCR and MPR rates were 33.3% and 50.0%, respectively. At a median follow-up of 27.2 months, the 2-year DFS rate was 77.4%. Grade≥3 treatment-related adverse events occurred in 13.3%. Achieving pCR was associated with higher baseline levels of CD8+ T cells and naïve-like T cells in both blood and TME. Elevated baseline CD8+ naïve-like T cells in both peripheral blood and tumor nests and their closer proximity to tumor cells correlated with improved DFS. Higher circulating baseline chemokine (C-C motif) ligand 3 (CCL3) levels were associated with both pCR and prolonged DFS. Postneoadjuvant treatment ctDNA positivity predicted shorter DFS, while longitudinal ctDNA monitoring identified relapse as early as 17.6 months before radiographic progression. CONCLUSIONS:Baseline CD8+ naïve-like T-cell abundance and spatial proximity to tumor cells, circulating CCL3 levels, and ctDNA dynamics may serve as potential prognostic biomarkers in resectable NSCLC receiving neoadjuvant camrelizumab plus chemotherapy. TRIAL REGISTRATION NUMBER:NCT06241807.

IntroductionInositol-requiring enzyme 1 alpha (IRE1α), encoded by endoplasmic reticulum (ER) to nucleus signaling 1 (Ern1) gene, is the most conserved sensor of ER stress. IRE1α-initiated signaling pathways contribute to functional maturation of secretory cells and have been implicated in various human diseases. In this study, we examined the roles of IRE1α in odontoblast development and dentin formation in wild-type mice as well as in DsppP19L mutant mice, which express a pathogenic variant of dentin sialophosphoprotein (P19L-DSPP) and exhibit a dentinogenesis imperfecta (DGI)-like phenotype.MethodsWestern-blotting and stains-all staining analyses were used to assess whether secretion of mutant P19L-DSPP was impaired in dental pulp cells containing odontoblasts from DsppP19L/P19L mice compared with Dspp+/+ controls. Immunohistochemistry and reverse-transcription PCR were performed to examine changes in IRE1α and its downstream target X-box binding protein 1 (XBP1) in P19L-DSPP mutant mice. To further investigate the roles of IRE1α in tooth development, we generated 2.3 Col1-Cre;Ern1fl/fl and compound 2.3 Col1-Cre;Ern1fl/fl;DsppP19L/+ mice. Structural and histological changes in mandibular molars were analyzed using plain X-ray radiography, micro-computed tomography (µCT), and histology. Additionally, in situ hybridization, quantitative real-time PCR, and immunohistochemistry were performed to compare molecular changes among these mice and Ern1fl/fl and Ern1fl/fl;DsppP19L/+ controls.ResultsWestern-blotting and stains-all staining analyses support that mutant P19L-DSPP protein was not efficiently secreted into dentin matrix and was accumulated within odontoblasts. Further, immunostaining signals for phosphorylated IRE1α and total XBP1 were dramatically increased in odontoblasts and other dental pulp cells of DsppP19L/+ and DsppP19L/P19L mice, in comparison with Dspp+/+ mice. Consistently, there was a small increase in spliced XBP1S protein and Xbp1s mRNA levels in P19L-DSPP mutant mice. Moreover, loss of IRE1α function reduced dentin formation in 2.3 Col1-Cre;Ern1fl/fl mice and exacerbated the dental defects of P19L-DSPP mutant mice. Notably, IRE1α deficiency did not restore the Dspp mRNA levels in the mutant mice but normalized the increased thickness of the dental pulp chamber floor dentin.ConclusionThese findings underscore the essential role of IRE1α in odontoblast function and dentinogenesis. Moreover, they reveal a context-dependent pathogenic role of IRE1α, providing new insights into ER stress in dental tissue development and disease.

Objective This study aimed to compare the clinical outcomes of midazolam and dexmedetomidine combined with ropivacaine-induced thoracic paravertebral nerve block (TPVB) in radical lung cancer surgery. Methods To retrospectively analyze the clinical data of elderly patients who underwent thoracoscopic radical lung cancer surgery from March 2020 to February 2023 in our hospital. All patients underwent a single two-site method of TPVB at the levels of T4 and T7 under ultrasound guidance. The patients were divided into midazolam group (0.25 % ropivacaine + 0.1 mg/kg midazolam) and dexmedetomidine group (0.25 % ropivacaine + 0.8 μg/kg dexmedetomidine) according to the application of sedative drugs, with 78 cases in each group. Ramsay sedation score, mean arterial pressure (MAP), heart rate (HR), electroencephalographic bispectral index (BIS), and blood oxygen saturation (SpO2), as well as the serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), epinephrine (E), cortisol (Cor), and norepinephrine (NE) were recorded at 6, 12, 24, 36 and 48 h postoperatively, respectively. The patients’ cognitive function was assessed using the Brief Mental State Evaluation Scale (MMSE) at 1 d preoperatively, 1 d postoperatively, and 7 d postoperatively. Results The amount of intraoperative sufentanil in the dexmedetomidine group was lower than that in the midazolam group (P < 0.05). The rate of atropine use was higher in the dexmedetomidine group than that in the midazolam group (P < 0.05). There was no significant difference in the occurrence of overall intraoperative adverse reactions (P > 0.05), but the incidence of respiratory depression in the dexmedetomidine group was significantly lower than that in the midazolam group, and the incidence of bradycardia in the dexmedetomidine group was significantly higher than that in the midazolam group (P < 0.05). At T0 ∼ T4, BIS and MAP showed a decreasing trend in both groups. 12, 24, 36 and 48 h postoperatively, the Ramsay sedation score was higher in the dexmedetomidine group than in the midazolam group (P < 0.05). At 36 and 48 h postoperatively, the serum Cor, E, NE, CRP, TNF-α, and IL-6 levels were lower in the dexmedetomidine group than in the midazolam group (P < 0.05). Compared with the preoperative 1d, the MMSE scores were significantly lower in both groups on one day postoperative, while the MMSE scores were significantly higher at postoperative day 7 than on postoperative day 1 (P < 0.05). At postoperative day 1, the MMSE score was significantly higher in the dexmedetomidine group than in the midazolam group (P < 0.05). The difference in the incidence of adverse events within 72 h postoperatively between the two groups was not statistically significant (3.95 % vs. 1.28 %, χ2 = 0.284, P = 0.594). Conclusion Dexmedetomidine compounded with ropivacaine-induced ultrasound-guided thoracic paravertebral nerve block is superior to midazolam for sedation, anti-inflammation, and anti-stress in elderly lung cancer patients.

BackgroundNeoadjuvant therapy is widely used for esophageal cancer (EC), but optimal treatment regimens and predictive factors for outcomes remain unclear. This study retrospectively analyzed data from EC patients who underwent neoadjuvant therapy.MethodsThe chi-square test or Fisher’s exact test was utilized to examine differences in general clinicopathological data between treatment benefit groups. Survival analyses were conducted using Kaplan-Meier methods. Cox univariate and multivariate regression analyses were employed to identify independent risk factors affecting overall survival (OS) in EC patients receiving different treatment modalities.ResultsThe study included 175 EC patients who underwent neoadjuvant therapy. Analysis of clinical benefit differences revealed that patients aged < 65 years (P = 0.028) and those with esophageal squamous cell carcinoma (ESCC) (P = 0.027) were more likely to achieve a complete response, while N1 patients more frequently attained an objective response (P < 0.001). OS analysis indicated that patients who did not receive immunotherapy exhibited better survival outcomes compared to those who did (P = 0.002). Patients with pretreatment N3 status demonstrated poorer survival compared to those with N0 (P = 0.004), N1 (P = 0.003), and N2 (P = 0.003) status. Among post-neoadjuvant EC patients who did not receive immunotherapy, those with primary tumors located in the middle esophagus (hazard ratio [HR], 0.181; 95% Confidence interval (CI) = 0.044-0.739; P = 0.017) and lower esophagus (HR, 0.163; 95%CI = 0.032-0.821; P = 0.028) demonstrated a better prognosis compared to patients with tumors in the upper esophagus. Notably, EC patients who did not receive immunotherapy after neoadjuvant therapy and underwent 3-6 cycles of therapy exhibited a poorer prognosis compared to those who received 1-2 cycles (HR, 2.731; 95%CI = 1.187-6.284; P = 0.018).ConclusionsIn conclusion, this study found that immunotherapy did not play a decisive role in neoadjuvant EC therapy. Instead, 1-2 cycles of chemotherapy or chemoradiotherapy were associated with a more favorable prognosis for these patients.

Upon endoplasmic reticulum (ER) stress, inositol-requiring enzyme 1 (IRE1) is activated, which subsequently converts an unspliced X-box binding protein 1 (XBP1U) mRNA to a spliced mRNA that encodes a potent XBP1S transcription factor. XBP1S is essential for relieving ER stress and secretory cell differentiation. We previously established Twist2-Cre;Xbp1CS/+ mice that constitutively expressed XBP1S in the Twist2-expressing cells as well as in the cells derived from the Twist2-expressing cells. In this study, we analyzed the dental phenotype of Twist2-Cre;Xbp1CS/+ mice. We first generated a mutant Xbp1s minigene that corresponds to the recombinant Xbp1Δ26 allele (the Xbp1CS allele that has undergone Cre-mediated recombination) and confirmed that the Xbp1s minigene expressed XBP1S that does not require IRE1α activation in vitro. Consistently, immunohistochemistry showed that XBP1S was constitutively expressed in the odontoblasts and other dental pulp cells in Twist2-Cre;Xbp1CS/+ mice. Plain X-ray radiography and µCT analysis revealed that constitutive expression of XBP1S altered the dental pulp chamber roof- and floor-dentin formation, resulting in a significant reduction in dentin/cementum formation in Twist2-Cre;Xbp1CS/+ mice, compared to age-matched Xbp1CS/+ control mice. However, there is no significant difference in the density of dentin/cementum between these two groups of mice. Histologically, persistent expression of XBP1S caused a morphological change in odontoblasts in Twist2-Cre;Xbp1CS/+ mice. Nevertheless, in situ hybridization and immunohistochemistry analyses showed that continuous expression of XBP1S had no apparent effects on the expression of the Dspp and Dmp1 genes. In conclusion, these results support that sustained production of XBP1S adversely affected odontoblast function and dentin formation.

AIM:To analyze and screen influencing factors of diabetic patients complicated with retinopathy,and establish and validate prediction model of nomogram. METHODS:A total of 1 252 patients from the Diabetes Complications Early Warning Dataset of the National Population Health Data Archive(PHDA)between January 2013 to January 2021 were selected and randomly divided into a modeling group(n=941)and a validation group(n=311).Univariate analysis,LASSO regression and Logistic regression analysis were used to screen out the influencing factors of diabetic retinopathy,and a nomogram prediction model was established.The receiver operating characteristic curve,Hosmer-Lemeshow test and calibration curve were used to evaluate the model.The clinical benefit was evaluated by the decision curve analysis(DCA). RESULTS:Age,hypertension,nephropathy,systolic blood pressure(SBP),glycated hemoglobin(HbA1c),high-density lipoprotein cholesterol(HDL-C),and blood urea(BU)were the influencing factors of diabetic retinopathy.The area under the curve(AUC)of the modeling group was 0.792(95％CI:0.763-0.821),and the AUC of the validation group was 0.769(95％CI:0.716-0.822).The Hosmer-Lemeshow goodness of fit test and calibration curve suggested that the theoretical value of the model was in good agreement(modeling group:x2=14.520,P=0.069;validation group:x2=14.400,P=0.072).The DCA results showed that the threshold probabilities range was 0.09-0.89 for modeling group and 0.07-0.84 for the validation group,which suggested the clinical net benefit was higher. CONCLUSION:This study constructed a risk prediction model including age,hypertension,nephropathy,SBP,HbA1c,HDL-C,and BU.The model has a high discrimination and consistency,and can be used to predict the risk of diabetic retinopathy in patients with diabetes.

Family with sequence similarity 20, member A (FAM20A) is a pseudo-kinase in the secretory pathway and is essential for enamel formation in humans. Here we examine if FAM20A is a membrane-associated protein. We show that the full-length FAM20A can be purified from HEK293 cells transfected with a FAM20A-expresing construct. Further, it is only found in the membrane fraction, but not in the soluble fraction, of cell lysate. Consistently, it is not secreted out of the expressing cells. Moreover, it is co-localized with GM130, a cis-Golgi network marker, and membrane topology analysis indicates that it has its C-terminus oriented towards the lumen of the organelle. Our results support that FAM20A is a Type II transmembrane protein within the secretory compartments.

e20074 Background: This study aimed to evaluate the safety and efficacy of neoadjuvant camrelizumab combined with chemotherapy in patients with resectable non-small cell lung cancer (NSCLC). Methods: In this single-arm phase II clinical trial, patients aged 18-75 with pathologically confirmed resectable stage IIIA-IIIB (T3-4N2) NSCLC without EGFR, ALK, and ROS1 gene mutations were enrolled since December 2022. Patients were assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2 or pemetrexed (for adenocarcinoma), 500mg/m2 plus platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5]). Radical surgery was performed within 4-6 weeks after neoadjuvant therapy. Patients undergo 18F-fluorodeoxyglucose (FDG) PET/CT scans within 1 week before treatment and surgery, respectively. The primary endpoints for follow-up are pathologic complete response (pCR) rate and major pathological response (MPR) rate, while secondary endpoints include safety and disease-free survival (DFS). Exploratory endpoints include molecular imaging research and biomarker analysis. Results: Up to December 2023, 30 patients (median age: 64 years) have been enrolled, including 22 cases of squamous carcinoma and 8 cases of adenocarcinoma. All patients received 3 cycles of neoadjuvant camrelizumab plus chemotherapy, and 27 patients underwent radical sugery. Three patients did not receive surgical treatment, 2 of whom refused surgery and 1 was unable to undergo surgery due to disease progression. Among patients received surgery, 27 (100%) achieved R0 resection, 10 (37.0%) achieved pCR, and 15 (55.6%) achieved MPR. For patients with squamous cell carcinoma, the MPR and pCR rates were 70% (14/20) and 45% (9/20), respectively, while for adenocarcinoma patients, the MPR and pCR rates were 14.3% (1/7) and 14.3% (1/7), respectively. There was no significant difference in pathological response rates between the PD-L1 tumor proportion score (TPS) ≥ 1% group and the PD-L1 TPS < 1% group. Most of treatment-related adverse events (TRAEs) were grade 1-2, and the most common TRAEs was leukopenia (63.0%). Five patients (18.5%) developed grade ≥ 3 TRAEs, including 3 leukopenia, 1 neutropenia, and 1 pneumonia. Biomarker analysis showed that among patients with pCR, the proportion of increased circulating M1 macrophages and decreased mononuclear myeloid-derived suppressor cells (M-MDSCs) and M2 macrophages after treatment was higher than those in non-pCR patients. Circulating ctDNA analysis showed that the ctDNA concentration of patients with non-pCR after treatment was higher than that of patients with pCR. Patients with ctDNA remaining positive after treatment were all in the non-pCR group. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy for NSCLC patients show promising pathological response rates and tolerable safety. Clinical trial information: NCT06241807 .

e20576 Background: Concurrent chemoradiation therapy (CRT) followed by durvalumab consolidation therapy has demonstrated significant survival benefit for unresectable stage III non-small cell lung cancer (NSCLC) in PACIFIC trial. However, there are still 20%-30% patients who have disease progression (PD) or intolerable toxicity. This prospective study aimed to evaluate safety and clinical activity of concurrent durvalumab plus CRT followed by durvalumab in unresectable stage III NSCLC (NCT04982549). Methods: This is a single-arm, open-label, multicenter phase II clinical trial and planned to enroll 35 patients with unresectable stage III NSCLC of any PD-L1 expression level and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All of patients will receive concurrent durvalumab 1500mg every 4 weeks plus SoC CRT followed by durvalumab monotherapy 1500mg every 4 weeks until PD or unacceptable toxicity. One cycle of induction durvalumab plus chemotherapy is allowed before radiotherapy upon investigator discretion. The primary endpoint is the incidence of grade ≥3 immune-mediated adverse event (AE). Here we report the preliminary clinical activity and safety of a preplanned interim analysis of this study. Results: By September 2022, 28 patients finished concurrent durvalumab plus CRT treatment and were included for analysis. 21 (75%) of 28 patients had radiographic tumor evaluation and entered the consolidation treatment stage, 7 (25%) patients discontinued treatment without radiographic tumor evaluation because of intolerable AE (5 patients) or withdrawing from the study (2 patients). 20 (71.4%) of 28 patients received one cycle induction therapy of durvalumab plus chemotherapy. The median age of these 28 patients was 64 years old, 26 (92.9%) of 28 patients with ECOG performance status of 1, and 14 (50%) of 28 patients were squamous carcinoma. Disease stage was IIIA (42.9%, 12/28), IIIB (39.3%, 11/28) and IIIC (17.9%, 5/28), with most of them (89.3%, 25/28) had N2/N3 lymphatic metastasis. 19 (90.5%) of 21 patients achieved objective response. Median interval from enrollment to the first radiological evaluation was 112 days. Grade ≥3 treatment-related adverse event (TRAEs) occurred in 13(46.4%) of 28 patients, including six (21.4%) possibly related to durvalumab. Conclusions: The interim results from CRUISER study showed promising clinical activity and manageable toxicity of durvalumab plus concurrent CRT followed by durvalumab for unresectable stage III NSCLC. The survival outcome and biomarker exploration will be analyzed upon data maturity. Phase 3 PACIFIC-2 study investigating clinical outcome of concurrent durvalumab plus CRT in unresectable NSCLC is ongoing. Clinical trial information: NCT04982549 .

Abstract Background The coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has led to a global pandemic in an unprecedented time frame. Systemic vascular involvement in COVID‐19 has been identified, and SARS‐CoV‐2 has also been found to cause multiple organ ischemia and posterior ocular segment disease in mammals, raising concerns about the human retinal microvascular involvement in SARS‐CoV‐2. Objective To objectively assess the presence of retinal microvascular impairment in COVID‐19 patients by optical coherence tomography angiography (OCTA), so as to facilitate the clinical system management of COVID‐19 patients. Methods We searched PubMed, Cochrane Library, EMBASE, Ovid, CBM to collect eligible studies. The main outcomes included the vessel density (VD), area or perimeter of foveal avascular zone (FAZ), central foveal thickness (CFT), subfoveal choroidal thickness (SCT) in our meta‐analysis. Results We eventually included five studies with a total of 401 participants. Our meta‐analysis showed that nonacute infectious COVID‐19 or post‐COVID‐19 patients presented significantly lower foveal VD of deep capillary plexus (WMD = −4.22, 95% CI [−8.00, −0.43]) and thinner SCT (WMD = −10.33, 95% CI [−19.08, −1.57]) than healthy controls. The foveal VD and parafoveal VD of superficial capillary plexus, parafoveal VD of deep capillary plexus, CFT, area, and perimeter of FAZ showed no significant differences between the groups. Conclusion The patients of nonacute infectious COVID‐19 or post‐COVID‐19 displayed alterations in the retinal microvasculature and choroidal vessels, including a significantly lower foveal VD in deep capillary plexus and thinner SCT. The impairment may be a medium to long‐term process. Close ophthalmic surveillance is necessary for COVID‐19 patients or post‐COVID‐19 patients.

BACKGROUND:The involvement of microRNA-338-5p in modulating NPC pathogenesis is still largely unknown, and this study aimed to investigate this issue.METHODS:The expressions of cancer associated genes were determined by Real-Time qPCR and Western Blot, and cell apoptosis was determined by flow cytometer (FCM). CCK-8 assay and colony formation assay were respectively used to determine cell proliferation and colony formation abilities. Transwell assay was used to evaluate cell migration. The expression levels of Ki67 protein in mice tissues were measured by Immunohistochemistry (IHC) assay.RESULTS:The present study found that microRNA-338-5p suppressed NPC progression by degrading its downstream target, Wnt family member 2B (WNT2B). Specifically, microRNA-338-5p tended to be low-expressed in NPC tissues and cell lines, compared to the non-tumor nasopharyngeal mucosa tissues and normal nasopharyngeal cell line (NP69). Upregulation of microRNA-338-5p inhibited proliferation, mobility, and epithelial-mesenchymal transition (EMT) in NPC cells in vitro, while silencing of microRNA-338-5p had opposite effects. Consistently, microRNA-338-5p suppressed tumorigenesis of NPC cells in vivo. In addition, microRNA-338-5p targeted WNT2B for degradation and inhibition, and the inhibiting effects of microRNA-338-5p overexpression on NPC development were reversed by upregulating WNT2B.CONCLUSIONS:Taken together, we concluded that microRNA-338-5p targeted WNT2B to hinder NPC development.

Upon endoplasmic reticulum (ER) stress, inositol-requiring enzyme 1 (IRE1) is activated and catalyzes nonconventional splicing of an unspliced X-box binding protein 1 (XBP1U) mRNA to yield a spliced XBP1 (XBP1S) mRNA that encodes a potent XBP1S transcription factor. XBP1S is a key mediator of the IRE1 branch that is essential for alleviating ER stress. We generated a novel mouse strain (referred to as "Xbp1(CS/+)" mice) that constitutively expressed XBP1S after Cre recombinase-mediated recombination. Further breeding of these mice with Twist2 Cre recombinase (Twist2-Cre) knock-in mice generated Twist2-Cre;Xbp1(CS/+) mice. Most Twist2-Cre;Xbp1(CS/+) mice died shortly after birth. Reverse-transcription polymerase chain reaction (RT-PCR) showed that constitutive expression of XBP1S occurred in various mouse tissues examined, but not in the brain. Immunohistochemistry confirmed that although the immunostaining signals for total XBP1 (XBP1U and XBP1S) were found in the calvarial bones in both Twist2-Cre;Xbp1(CS/+) and control mice, the signals for XBP1S were only detected in the Twist2-Cre;Xbp1(CS/+) mice, but not in the control mice. These results suggest that a precise control of XBP1S production is essential for normal mouse development.

Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein that is highly expressed in odontoblasts, but only transiently expressed in presecretory ameloblasts during tooth development. We previously generated a knockin mouse model expressing a mouse equivalent (DSPP, p.P19L) of human mutant DSPP (p.P17L; referred to as “DsppP19L/+”), and reported that DsppP19L/+ and DsppP19L/P19L mice manifested a dentin phenotype resembling human dentinogenesis imperfecta (DGI). In this study, we analyzed pathogenic effects of mutant P19L-DSPP on enamel development in DsppP19L/+ and DsppP19L/P19L mice. Micro-Computed Tomography (μCT) analyses of 7-week-old mouse mandibular incisors showed that DsppP19L/P19L mice had significantly decreased enamel volume and/or enamel density at different stages of amelogenesis examined. Acid-etched scanning electron microscopy (SEM) analyses of mouse incisors demonstrated that, at the mid-late maturation stage of amelogenesis, the enamel of wild-type mice already had apparent decussating pattern of enamel rods, whereas only minute particulates were found in DsppP19L/+ mice, and no discernible structures in DsppP19L/P19L mouse enamel. However, by the time that incisor enamel was about to erupt into oral cavity, distinct decussating enamel rods were evident in DsppP19L/+ mice, but only poorly-defined enamel rods were revealed in DsppP19L/P19L mice. Moreover, μCT analyses of the mandibular first molars showed that DsppP19L/+ and DsppP19L/P19L mice had a significant reduction in enamel volume and enamel density at the ages of 2, 3, and 24weeks after birth. Backscattered and acid-etched SEM analyses revealed that while 3-week-old DsppP19L/+ mice had similar pattern of enamel rods in the mandibular first molars as age-matched wild-type mice, no distinct enamel rods were observed in DsppP19L/P19L mice. Yet neither DsppP19L/+ nor DsppP19L/P19L mice showed well-defined enamel rods in the mandibular first molars by the age of 24weeks, as judged by backscattered and acid-etched SEM. In situ hybridization showed that DSPP mRNA level was markedly reduced in the presecretory ameloblasts, but immunohistochemistry revealed that DSP/DSPP immunostaining signals were much stronger within the presecretory ameloblasts in Dspp mutant mice than in wild-type mice. These results suggest that mutant P19L-DSPP protein caused developmental enamel defects in mice, which may be associated with intracellular retention of mutant DSPP in the presecretory ameloblasts.

The sudden outbreak of COVID-19 has placed an unprecedented pressure on China's public health system. It is imperative to strengthen the capacity of early surveillance and early warning to build a sound public health system. Therefore, it is necessary to improve the multi-channel monitoring and early warning mechanism to improve the ability of real-time analysis and judgment. To explore the correlation of COVID-19 spread with Baidu search data in Beijing, so as to evaluate the possibility of monitoring the epidemic situation of COVID-19 with Baidu search data. This study compared the daily case counts of COVID-19 outbreak from January 20 to March 1, 2020 with Baidu search data for the same period in Beijing. After keyword selection, filtering and composition, the most correlated lag of the COVID-19 Baidu Search Index (CBSI) was used for comparison and linear regression model development. Our findings showed a positive relationship of CBSI and the confirmed cases of COVID-19 (ρ=0.711, P < .001). The strongest correlation between COVID-19 confirmed cases and indices, CBSI, was at a lag of -11 days. The regression coefficient β1 of the established regression model was equal to 1.042 (P<.001), R2 was equal to 0.7, which indicated that Baidu search data could reflect 70% of the variation in COVID-19 cases. COVID-19 Baidu Search index may be a good monitoring indicator for early detection of COVID-19 outbreaks.

OBJECTIVE PD-1/PD-L1 inhibitors are a relatively new class of immunotherapeutic drugs approved for advanced non-small-cell lung cancer. The purpose of this study was to conduct a network meta-analysis to compare the safety and efficacy of these immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS We used Bayesian network meta-analysis methods to evaluate the efficacy and safety of the included treatments. We further analyzed subgroups based on PD-L1 expression level, histology type, and line of the treatment setting. RESULTS We identified 19 RCTs, including 12,753 patients. In the analysis of all-comers, the pembrolizumab/chemotherapy combination ranked best for overall survival (OS) and progression-free survival (PFS). Durvalumab was the only ICI treatment that showed no benefit over chemotherapy. In the first-line setting only, in terms of OS, atezolizumab, pembrolizumab/chemotherapy, and nivolumab/ipilimumab ranked as the best treatments for patients with PD-L1 expression levels of ≥50%, 1-49%, and <1%, respectively. Nivolumab, atezolizumab, pembrolizumab, and durvalumab all had lower odds of grade 3 or greater treatment-related adverse events (TRAEs) compared to chemotherapy. With the addition of chemotherapy to any ICI regimen, the odds of TRAEs increased in a considerable and statistically significant way. CONCLUSIONS While the pembrolizumab/chemotherapy combination was the most effective therapy in the overall cohort of all-comers, treatment preferences varied by treatment-line setting, tumor characteristics, and outcome of interest. In the first-line setting, the most effective treatments for patients with PD-L1 expressions of ≥50%, 1-49%, and <1% were atezolizumab, pembrolizumab/chemotherapy, and nivolumab/ipilimumab, respectively.

Background: Myopia has become a worldwide public health issue, which is occurring at a younger age, leading to an increased risk of high myopia. Ocular complications associated with high myopia can lead to irreversible vision loss. It is urgent and critical to explore effective treatment to slow down or even stop the progression of myopia in young children. Objective: The aim of the study was to evaluate the additive effects of orthokeratology (OK) and 0.01% atropine ophthalmic solution for myopia in children. Methods: We searched PubMed, Cochrane Library, EMBASE, MEDLINE, Web of science, Ovid, EBSCO host, CNKI, and CBM to collect eligible studies. Efficacy and safety were evaluated in terms of the axial length (AL), uncorrected distant visual acuity (UCVA), corneal endothelial cell density (CECD), and intraocular pressure (IOP). We calculated the weighted mean difference (WMD) and the 95% confidence intervals (CIs) of all outcomes and plotted on forest plots. Results: Four studies were ultimately included, involving a total of 267 subjects. This meta-analysis revealed that the mean AL of the subjects in the experimental group was 0.09 mm less than that of subjects in the control group (WMD = −0.09, 95% CI [−0.15, −0.03], p = 0.003). There was no significant difference in UCVA, CECD, and IOP between the 2 groups (WMD was −0.01 [95% CI: −0.03, 0.01], 11.75 [95% CI: −4.09, 27.58], 0.12 [95% CI: −0.40, 0.63], respectively). None of the studies reported severe adverse events. Conclusion: Our study suggests that the combination of OK and 0.01% atropine is more effective in slowing axial elongation than OK monotherapy in children with myopia in a relatively short duration of treatment. In addition, the combination therapy has no negative influence on UCVA, CECD, and IOP.

Background Esophageal squamous cell carcinoma (ESCC) is among the leading causes of cancer mortality, especially in China. Advances in technology have resulted in significant clinical gains in the treatment of ESCC, with more precise radiotherapy now considered an integral part of standard patient care, either alone or in combination with chemotherapy. Though, a better understanding of tumoral radiosensitivity is still needed in order to develop strategies and further personalize radiation treatments. Methods We carried out whole-exome sequencing (WES) on paired tumors collected before and after radiotherapy from 11 patients with ESCC. A comprehensive analysis was performed to compare the somatic mutations, the driver genes mutations, the copy number variations (CNVs), the mutational signatures, the tumor’s clonal composition, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway between pre- and post-radiotherapy samples in this cohort. Results According to the analysis of WES results, more insertion/deletion mutations (indels) were discovered in the post-radiotherapy samples than in the pre-radiotherapy samples (Wilcoxon rank-sum test, P=0.014). The mutation rate of driver gene Ephrin-A2 (EPHA2) was significantly reduced after radiotherapy (Fisher’s exact test, P=0.035). However, comparison between the pre- and post-radiotherapy groups reveals no significant differences in other content. Conclusions Our study revealed the overall genomic profile of ESCC before and after radiotherapy and determined that a loss of EPHA2 mutations might make cancer cells resistance to radiotherapy.

Two new coordination polymers (CPs), namely [Cu(4-bptzp)(1,3-BDC)]n (1, 1,3-H2BDC = 1,3-benzenedicarboxylic acid, 4-bptzp = 1,4-bis(5-(4-pyridyl)tetrazolyl)propane) and [Co(4-bptzh)(1,3-BDC)]n (2, 4-bptzh = 1,4-bis(5-(4-pyridyl)tetrazolyl)hexane) were prepared by hydrothermal reactions of the corresponding metal salts with the 1,3-H2BDC in the presence of different flexible bis(pyridyl-tetrazole) ligands. The inhibitory effect of compounds 1 and 2 on SK-OV-3 human ovarian cancer cells was assessed. Firstly, the CCK-8 assay was performed and the anti-proliferation activity of compounds 1 and 2 was assessed. Then, the Annexin V-FITC/PI apoptosis assay was performed to detect the apoptosis of the cancer cells in flow cytometry.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in China. This study aimed to develop a hyaluronic acid (HA) decorated, pH sensitive lipid-polymer hybrid nanoparticles (LPH NPs) to co-deliver erlotinib (ERL) and bevacizumab (BEV) (HA-ERL/BEV-LPH NPs) for targeting and suppressing NSCLC. HA contained pH sensitive nano-materials were synthesized by acylation reaction. HA-ERL/BEV-LPH NPs were prepared using a sonication method. To explore the efficiency of the system, we evaluated the physicochemical parameters and performed a release study, a cellular uptake assay, a cytotoxicity evaluation, and several in vivo anti-tumor studies in comparison with free drugs and single drug systems. All LPH NPs samples have particle sizes of about 100−120 nm, polydispersity index values range from 0.12 to 0.15, and negative zeta potentials. HA-ERL/BEV-LPH NPs contained pH sensitive adipic acid dihydrazide (ADH) showed fast drug release at pH 5.5 than pH 7.4. After 21 days, the tumor volume of the HA-ERL/BEV-LPH NPs group (229.2 ± 13.1 mm3) was significantly smaller than 0.9 % NaCl control group (1126.3 ± 39.4 mm3), with a tumor inhibition rate of 79.7 ± 3.2 %. The maximum plasma ERL concentrations, half life period, and area under the curve of HA-ERL/BEV-LPH NPs were 21.6 μg/mL, 7.57 h, and 290.3 mg/L·h). With the highest tumor tissue accumulation concentration (25.3 μg/mL) and low system toxicity, HA-ERL/BEV-LPH NPs. HA-ERL/BEV-LPH NPs could be used as a promising system for the combination therapy of NSCLC.