[Clinical Characteristics and Survival Analysis of Single Center Adult Chronic Myeloid Leukemia in Chronic Phase].

OBJECTIVE: To investigate the clinical characteristics and prognosis of single center adult chronic myeloid leukemia in chronic phase (CML-CP). METHODS: Clinical data of 41 adult CML-CP patients in Department of Hematology, Shanghai Fengxian District Central Hospital from January 2015 to May 2021 were retrospectively analyzed. The clinical characteristics and prognosis of patients between <60 years group and ≥60 years group were compared. RESULTS: The 41 patients included 27 (65.9%) males and 14 (34.1%) females. The median age of the patients was 56(19-84) years, with 22 cases (53.7%) <60 years and 19 cases (46.3%) ≥60 years. Univariate analysis indicated that the proportions of patients with comorbidities, intermediate/high-risk Sokal score, myelofibrosis, and lactate dehydrogenase ≥1 000 U/L were significantly increased in ≥60 years group compared with <60 years group at initial diagnosis (all P <0.05). There were no statistical differences in the distribution of sex, ELST score, white blood cell count, platelet count, peripheral blood basophil percentage, peripheral blood eosinophil percentage and bone marrow primitive cell percentage between the two groups (P >0.05). The proportion of patients taking reduced-dose imatinib in ≥60 years group significantly increased (P <0.001). Patients <60 years had a higher proportion of molecular biological remission after treatment of tyrosine kinase inhibitors (TKIs) than patients ≥60 years (P <0.001). The incidence of non-hematologic adverse reactions to TKI therapy significantly increased in patients ≥60 years (P <0.001). Multivariate analysis showed that no adverse factors affecting the efficacy and prognosis of TKI. CONCLUSION: Compared with adult CML-CP patients <60 years, patients ≥60 years gain fewer benefits from TKI treatment and increased adverse reactions.

Impact of the orofacial muscular rehabilitation exercise on facial expression recovery post-orthognathic surgery.

OBJECTIVE: This study aimed to evaluate the impact of myofunctional rehabilitation of the orofacial muscles through specific exercises on the recovery of facial expression in patients following orthognathic surgery. MATERIAL AND METHODS: The study included 62 patients who underwent Le Fort I and sagittal split ramus osteotomy (SSRO). Patients were divided into two groups: the first group started immediate post-operative myofunctional rehabilitation of the orofacial muscles through specific exercises. In contrast, patients in Group II did not undergo any myofunctional rehabilitation post-operative exercises. The recovery of facial expressions postoperatively was evaluated in both calm and smiling states by comparing the differences between 3D facial scanning data of chosen facial anatomical structures collected at five key time points: pre-surgery (D0), 2 days (D2), 14 days (D14), 1 month (D30), and 3 months (D90) postoperatively. RESULTS: The analysis revealed that characteristic angles and lengths experienced significant changes post-surgery, with ∠chRnchL and ∠chRsnchL decreasing at D2 and normalizing by D30 in the experimental group, while the control group showed a slower recovery, normalizing by D90. The ChL-R length decreased at D2, returning to normal by D30 in the experimental group and D90 in the control group. The height Li-Ls increased at D2 and normalized by D30 in calm and smiling expressions across single and double jaw surgery patients. These findings underscore the more rapid recovery in the experimental group compared to the control group (P < 0.05; P < 0.005; P < 0.0001). CONCLUSION: Initiating myofunctional rehabilitation immediately following orthognathic surgery enhances facial muscle function recovery, improves patient confidence, and expedites social reintegration. This approach is crucial for functional and psychological benefits.

Epidemiology and genotypes analysis of human papillomavirus infection in Huizhou, China.

Background: Human papillomavirus (HPV) is a main pathogenic factor for cervical carcinoma. The prevalence and genotypes distribution of HPV vary in different regions. Thus, our study aimed to investigate the epidemiology of HPV in Huizhou, China. Methods: HPV tests were detected in 5,325 female outpatients, we focused on the overall HPV prevalence, genotypes distribution, and the correlation of HPV genotypes with cervical cytology. Results: The overall HPV prevalence was 27.53%, HPV52, HPV58, HPV39, HPV16 and HPV51 were predominant genotypes with single infection rate of 70.80%. HPV infection rate showed a U-shaped age distribution, statistical differences were observed among 5 age groups (χ2 = 50.497, p < 0.01), and the higher positive rate was aged under 30 (34.42%) and above 60 (34.74%). Among high-risk HPV (hrHPV) infections, 60.69% involved NILM, 0.99% HSIL. The degrees of cervical lesions in multiple hrHPV infections were worse than those in single infection (p < 0.01). Conclusion: The HPV infection rate is high in Huizhou, Guangdong, single infection was predominant. HPV infection presented with a U-shaped age distribution. Multiple hrHPV infection was worrying since it may aggravate cervical lesions. Women should pay more attention to HPV detection and choose a more appropriate HPV vaccine according to local HPV type distribution.

Insights into the prognostic value and immunological role of CD74 in pan-cancer.

BACKGROUND: CD74 is a non-polymorphic type II transmembrane glycoprotein. It is involved in the regulation of T and B cell development, and dendritic cell (DC) motility. Numerous studies have found that CD74 exerts an essential role in tumor immunity, but the expression profile of CD74 is still not systematically reported, and its value in human pan-cancer analysis is unknown. In this study, we analyzed the expression pattern of CD74 in 33 cancers, and evaluated the significance of CD74 in prognosis prediction and cancer immunity. METHODS: Pan-cancer dataset from UCSC Xena.We used the Sangerbox website combined with R software' Timer, CIBERSORT method and IOBR package to analyze and plot the data. Survival was assessed using the Kaplan-Meier method and log-rank test for 33 cancer types (p < 0.05). In addition, to explore the relationship between CD74 expression and immune checkpoints, immune cell infiltration, tumor mutational burden (TMB) and microsatellite instability (MSI), Spearman correlation analysis was performed. RESULTS: This study comprehensively analyzed CD74 expression in 33 different tumor types, revealing that CD74 play an crucial role in cancer formation and development. CONCLUSIONS: CD74 gene expression in different cancers is associated with immune cell infiltration and immunomodulators and may provide a promising target for survival and immunotherapy. Our study shows that CD74 has an essential role as a biomarker of prognosis during tumor development, which highlights the possibility of new targeted therapies.

Targeting ONECUT2 inhibits tumor angiogenesis via down-regulating ZKSCAN3/VEGFA.

OC-2 plays a vital role in tumor growth, metastasis and angiogenesis, but molecular mechanism how OC-2 regulates angiogenic factors is unclear. We found that OC-2 was highly expressed in HepG2, COLO, MCF-7, SKOV3 cells and rectum carcinoma tissues, and angiogenic factors levels were positively related to OC-2. Then OC-2 KD inhibited the tumor growth, metastasis and angiogenesis process in vitro and vivo. ChIP-Seq showed that 228 target genes of OC-2 were identified and they were associated with tumor growth, metastasis, angiogenesis and signal transduction; OC-2 bound to ZKSCAN3 at promoter region. Luciferase assays showed that ZKSCAN3 was identified as target gene of OC-2 and VEGFA was identified as target gene of ZKSCAN3; OC-2 promoted VEGFA expression via activating ZKSCAN3 transcriptional program. Importantly, OC-2 KD down-regulated VEGFA secretion to suppress tumor angiogenesis of HUVECs. Besides VEGFA, OC-2 was positively correlated with other angiogenic factors HIF-1α, FGF2, EGFL6 and HGF. Meanwhile, ERK1/2 and Smad1 signaling pathways might be related to function of OC-2 driving tumor aggressiveness. We revealed that OC-2 might regulate tumor growth, metastasis, angiogenesis via ERK1/2, Smad1 signaling pathways and regulate VEGFA expression for tumor angiogenesis via activating ZKSCAN3 transcriptional program, indicating that OC-2 was a convincing target to develop novel anti-tumor drugs based on angiogenesis.

Downregulation of S100A11 promotes T cell infiltration by regulating cancer-associated fibroblasts in prostate cancer.

OBJECTIVE: This study aims at revealing the relationship between S100A11 and cancer-associated fibroblasts (CAFs) in prostate cancer and improving T cell infiltration into solid tumors. METHODS: H&E, IHC and Sirius red staining were used to detect the stroma content in prostate cancer tissues. Stable S100A11 knockdown cell lines DU 145, 22Rv1, RM-1 and NOR-10 were established by lentivirus transfection. Co-culture system of RM-1 and CAFs was established. CCK-8, wound healing and transwell were proceeded to determine proliferation, migration and invasion of prostate cancer cells. Stably knocked-down RM-1 and CAFs were co-injected into C57BL/6 mice to detect the role of S100A11 in vivo. CAFs, CD4+ T cell and CD8+ T cell in these tumors were assessed by IF. T cell profile was analyzed by flow cytometry. RESULTS: A significant amount of stroma exists in prostate cancer tissues. Downregulation of S100A11 inhibits proliferation, migration and invasion of human prostate cancer cells in vitro, and suppresses the expression of cancer-associated fibroblasts (CAFs) in vivo. Knockdown of S100A11 enhances the inhibitory effect of Erdafitinib on CAFs in both the co-culture system and in vivo. The combined knockdown of S100A11 in tumor cells and CAFs shows a superior therapeutic effect compared to the individual knockdown in tumor cells alone. Knockdown of S100A11, both in RM-1 and CAFs, combined with Erdafitinib treatment reduces tumorigenicity by suppressing the content of CAFs and increasing the infiltration of CD4+ T cell and effective CD8+ T cell in tumor. CONCLUSION: Downregulation of S100A11 plays a crucial role in enhancing the therapeutic response to Erdafitinib and reversing immunosuppressive tumor microenvironment.

Diallyl Disulfide Blocks Cigarette Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced Lung Tumorigenesis via Activation of the Nrf2 Antioxidant System and Suppression of NF-κB Inflammatory Response.

Chemoprevention is a potential strategy to reduce lung cancer incidence and death. Recently, we reported that garlic oil significantly inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis. Diallyl disulfide (DADS) is a bioactive ingredient in garlic. Our goal was to examine the chemopreventive effectiveness and mechanism of DADS on NNK-triggered lung cancer in vivo and in vitro in the current investigation. The results indicated that DADS significantly reduced the number of lung nodules in the NNK-induced A/J mice. Consistent with the in vivo results, DADS markedly inhibited NNK-induced decrease of MRC-5 cells' viability. Mechanistically, DADS could promote Nrf2 dissociated from the Keap1-Nrf2 complex and accelerate Nrf2 nuclear translocation, which in turn upregulates its downstream target genes. Besides, DADS further inhibited the NF-κB signaling cascade, thus reducing the accumulation of inflammatory factors. Collectively, these discoveries supported the potential of DADS as a novel candidate for the chemoprevention of tobacco-carcinogen-induced lung cancer.

Molecular cloning and characterization of endoplasmic reticulum stress related genes grp78 and atf6α from black seabream (Acanthopagrus schlegelii) and their expressions in response to nutritional regulation.

Glucose-regulated protein 78 (grp78) and activating transcription factor 6α (atf6α) are considered vital endoplasmic reticulum (ER) molecular chaperones and ER stress (ERS) sensors, respectively. In the present study, the full cDNA sequences of these two ERS-related genes were first cloned and characterized from black seabream (Acanthopagrus schlegelii). The grp78 cDNA sequence is 2606 base pair (bp) encoding a protein of 654 amino acids (aa). The atf6α cDNA sequence is 2168 base pair (bp) encoding a protein of 645 aa. The predicted aa sequences of A. schlegelii grp78 and atf6α indicated that the proteins contain all the structural features, which were characteristic of the two genes in other species. Tissues transcript abundance analysis revealed that the mRNAs of grp78 and atf6α were expressed in all measured tissues, but the highest expression of these two genes was all recorded in the gill followed by liver/ brain. Moreover, in vivo experiment found that fish intake of a high lipid diet (HLD) can trigger ERS by activating grp78/Grp78 and atf6α/Atf6α. However, it can be alleviated by dietary betaine supplementation, similar results were also obtained by in vitro experiment using primary hepatocytes of A. schlegelii. These findings will be beneficial for us to evaluate the regulator effects of HLD supplemented with betaine on ERS at the molecular level, and thus provide some novel insights into the functions of betaine in marine fish fed with an HLD.

Formin-like 2 promotes angiogenesis and metastasis of colorectal cancer by regulating the EGFL6/CKAP4/ERK axis.

Increasing evidence indicates that angiogenesis plays a pivotal role in tumor progression. Formin-like 2 (FMNL2) is well-known for promoting metastasis; however, the molecular mechanisms by which FMNL2 promotes angiogenesis in colorectal cancer (CRC) remain unclear. Here, we found that FMNL2 promotes angiogenesis and metastasis of CRC in vitro and in vivo. The GDB/FH3 domain of FMNL2 directly interacts with epidermal growth factor-like protein 6 (EGFL6). Formin-like 2 promotes EGFL6 paracrine signaling by exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. Epidermal growth factor-like protein 6 binds to the N-terminus of CKAP4 to promote the migration of HUVECs by activating the ERK/MMP pathway. These findings suggest that FMNL2 promotes the migration of HUVECs and enhances angiogenesis and tumorigenesis in CRC by regulating the EGFL6/CKAP4/ERK axis. Therefore, the EGFL6/CKAP4/ERK axis could be a candidate therapeutic target for CRC treatment.

An accurate prediction of the origin for bone metastatic cancer using deep learning on digital pathological images.

BACKGROUND: Determining the origin of bone metastatic cancer (OBMC) is of great significance to clinical therapeutics. It is challenging for pathologists to determine the OBMC with limited clinical information and bone biopsy. METHODS: We designed a regional multiple-instance learning algorithm to predict the OBMC based on hematoxylin-eosin (H&E) staining slides alone. We collected 1041 cases from eight different hospitals and labeled 26,431 regions of interest to train the model. The performance of the model was assessed by ten-fold cross validation and external validation. Under the guidance of top3 predictions, we conducted an IHC test on 175 cases of unknown origins to compare the consistency of the results predicted by the model and indicated by the IHC markers. We also applied the model to identify whether there was tumor or not in a region, as well as distinguishing squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumor. FINDINGS: In the within-cohort, our model achieved a top1-accuracy of 91.35% and a top3-accuracy of 97.75%. In the external cohort, our model displayed a good generalizability with a top3-accuracy of 97.44%. The top1 consistency between the results of the model and the immunohistochemistry markers was 83.90% and the top3 consistency was 94.33%. The model obtained an accuracy of 98.98% to identify whether there was tumor or not and an accuracy of 93.85% to differentiate three types of cancers. INTERPRETATION: Our model demonstrated good performance to predict the OBMC from routine histology and had great potential for assisting pathologists with determining the OBMC accurately. FUNDING: National Science Foundation of China (61875102 and 61975089), Natural Science Foundation of Guangdong province (2021A15-15012379 and 2022A1515 012550), Science and Technology Research Program of Shenzhen City (JCYJ20200109110606054 and WDZC20200821141349001), and Tsinghua University Spring Breeze Fund (2020Z99CFZ023).

A canine model of aortic arch aneurysm created with autologous pericardium.

Background: To establish a canine model of aortic arch aneurysm that is suitable for research on new devices and techniques applied to the aortic arch. Materials and methods: Fifteen mongrel dogs underwent surgery. The autologous pericardial patch was sewn on the aortotomy site in the anterior wall of the aortic arch. The animals were followed up for 3 months postoperatively. Computed tomography angiography was used to visualize and measure the aneurysm model. Hematoxylin and eosin staining was used to observe the histological characteristics of the aneurysm model. Changes in aneurysm diameter over time were analyzed using analysis of variance. Results: One dog died of hemorrhage during surgery. Fourteen dogs survived the surgical procedure. Two of them died on the first postoperative day because of ruptures at the suturing margin. The diameter of the aneurysm model was twice as large as that of the aortic arch. There was no significant change in the maximum diameter of the aneurysm model during the follow-up period. Conclusions: We established a controllable and stable aortic arch aneurysm model created with an autologous pericardium patch. The aneurysm model can be used to research endoleaks after thoracic endovascular aortic repair and new endovascular techniques can be applied to the aortic arch.

Preparation of DSPE-PEG-cRGD Modified Cationic Liposomes for Delivery of OC-2 shRNA and The Antitumor Effects on Breast Cancer.

Cationic liposome delivery of interfering RNA (shRNA) plays an important role in tumor therapy. The cyclic Arg-Gly-Asp (cRGD) modified cationic liposomes (cRGD-CL) were designed for targeted delivery of ONECUT2 (OC-2) shRNA (pshOC-2) to breast cancer cells. The characterization analysis of cationic liposome showed that the prepared cRGD-CL/pshOC-2 lipoplexes had uniform particle size (150 ± 1.02 nm), moderate zeta potential (19.8 ± 0.249 mV) and high encapsulation efficiency (up to 96%). The results of flow cytometer showed that the introduction of cRGD could significantly promote the liposomes targeting tumor cells. In MCF-7 cells, the pshOC-2 could down-regulate expression of OC-2 and result in cell apoptosis, inhibition of the wound healing, migration and cell colony formation, in which the signal pathways of Bcl-xL, Bcl-2 were inhibited and the signal pathways of Bax and Cleaved Caspase-3 were promoted. In MCF-7 xenograft mice, intravenous administration of cRGD-CL/pshOC-2 lipoplexes could effectively reduce the expression of OC-2 in tumors and result in apparently antitumor effects, which suggested that the lipoplexes might be deeply penetrated into tumor through receptor-mediated transcytosis. The results revealed that the cationic liposome (cRGD-CL) was an effective delivery system for OC-2 shRNA, which might be an effective therapeutic candidate for breast cancer.

[Correlation between Expression of CD47 Molecule in Patients with Newly Diagnosed Adult Acute Myeloid Leukemia and Clinical Prognosis].

OBJECTIVE: To investigate the expression of CD47 molecules in patients with newly diagnosis of adult acute myeloid leukemia (AML) and its correlation with clinical prognosis. METHODS: 20 patients with acute myeloid leukemia diagnosed in Shanghai Fengxian District Central hospital from April 2020 to October 2021 and 5 cases with non malignant hematological diseases in the control group were collected, and the expression of CD47 in single nuclear cells of bone marrow and peripheral blood was detected by real-time fluorescence quantitative polymerase chain reaction (qPCR). Combined with the blood image, bone marrow smears, flow cytometry, chromosome and gene detection, ECOG score, etc. during the patient's initial diagnosis, the relationship between the patient's prognosis and CD47 was evaluated. RESULTS: The expression of CD47 in bone marrow (P=0.0115) and peripheral blood mononuclear cells (P=0.0069) in new diagnosis AML patients was significantly higher than that of controls. In bone marrow mononuclear cells, the total survival time of patients with high CD47 expression was less than that of CD47 low expression patients (P=0.036). There was statistical significance in difference stratification group (P=0.012), but there was no statistical significance between CD47 expression and survival time in peripheral blood mononuclear cells (P=0.116). There were no statistical significance between bone marrow mononuclear cell CD47 expression and gene mutation fusion genes related to leukemia , CD34+, CD38+, CD123+ (P>0.05). The proportion of bone marrow protocells in AML patients was >50%, the ECOG score was >2 points, MLLELL fusion gene and chromosome prognosis stratification were all risk factors affecting the survival of patients (P=0023, 0.036, 0.012, 0.001, respectively). The high expression of bone marrow CD47 in AML patients indicated a high risk of recurrence (P=0.017). CONCLUSION: The high expression of bone marrow mononuclear cell CD47 in AML patients indicates poorer survival and higher risk of recurrence.

Digital technology for orthognathic surgery training promotion: a randomized comparative study.

Background: This study aims to investigate whether a systematic digital training system can improve the learning efficiency of residents in the first-year orthognathic surgery training course and evaluate its effectiveness in teaching orthognathic surgery. Methods: A digital training system was applied, and a comparative research approach was adopted. 24 first-year orthognathic surgery residents participated in the experiment as part of their professional skill training. The Experimental group was required to use a digital training system, and the Control group was trained in lectures without digital technologies. Three indicators, including theoretical knowledge and clinical operation, were assessed in tests, and evaluations from instructors were analyzed to evaluate learning efficiency. Results: The results showed that the scores in theoretical tests, practical operations, and teacher evaluations, the Experimental groups were all higher than the Control group (P = 0.002 for anatomy, P = 0.000 for operation theory) after using digital technology, except for the understanding of complications (P = 0.771). In addition, the questionnaire survey results showed that the study interest (P = 0.001), self-confidence (P = 0.001), satisfaction (P = 0.002), and academic performance (P = 0.001) of the residents of the Experimental group were higher than those of the Control group. Conclusions: The outcomes indicated that the digital training system could benefit orthognathic residents' learning efficiency, and learning interest and teaching satisfaction will also improve.

Orofacial myofunctional changes in skeletal Class III patients after bimaxillary orthognathic surgery.

The aim of this study is to investigate the effect of bimaxillary orthognathic surgery on orofacial myofunctional changes in skeletal class III patients. 35 patients who received Le Fort I maxillary advancement osteotomy and mandibular SSRO setback were included in this study. Facial expression function was analyzed by "placid" or "smile" expressions using chL-chR, ∠chRnchL, and ls-li. Occlusal force and balance were analyzed using a T-scan III digital occlusal analysis system. Maximum mouth opening (MMO) was measured prior to surgery and 2/14/28/42/90/180/360 days after surgery. After surgery, patients recovered facial expressions in no less than 3 months for both the "placid" or "smile" facial expression. Patients obtained significantly improved 'smile' expressions 3 months after the operation compared to preoperative "smiles", and this improvement remained stable 12 months after the operation. Occlusal force was significantly decreased with the balance of occlusion lost immediately after surgery. These conditions gradually recovered, and patients finally obtained a more balanced and stronger occlusion [occlusion balance: 6.7 ± 2.7 mm vs. 4.1 ± 3.0 mm (day -7 vs. day 42); occlusion force: 19.6 ± 7.0 kg vs. 24.2 ± 9.3 kg (day -7 vs. day 180)]. However, patients had smaller postoperative mouth opening compared to preoperation opening during our follow-up. Our results confirmed that orthognathic surgery obstructs orofacial myofunctions of skeletal class III patients in the short-term. In the long-term, orthognathic surgery results in more stable and balanced orofacial myofunctions. By understanding the process of functional recovery of orofacial muscles after orthognathic surgery, we hope to accelerate patient's recovery from surgery.

HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease.

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima-media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.

Structural insights into ligand recognition and selectivity of somatostatin receptors.

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Activation of the human chemokine receptor CX3CR1 regulated by cholesterol.

As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and neuropathy. However, the drug development of CX3CR1 is hampered partially by the lack of structural information. Here, we present two cryo-electron microscopy structures of CX3CR1-Gi1 complexes in ligand-free and CX3CL1-bound states at 2.8- and 3.4-Å resolution, respectively. Together with functional data, the structures reveal the key factors that govern the recognition of CX3CL1 by both CX3CR1 and US28. A much smaller conformational change of helix VI upon activation than previously solved class A GPCR-Gi complex structures is observed in CX3CR1, which may correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling transduction. Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein-coupled receptor) signaling and provide insights into the diversity of G protein coupling.

Comparison of the Accuracy of Maxillary Repositioning Between Using Splints and Templates in 2-Jaw Orthognathic Surgery.

PURPOSE: Printed cutting and repositioning templates could bring superior accuracy when transferring a maxillary plan to the operating room compared to a wafer-based method. However, the effect of these methods in different types of cases is inconclusive. The objective of the study was to compare the accuracy when using printed occlusal splints versus templates in simple and complicated cases. METHODS: A retrospective cohort study design was used. Complicated cases were defined as cases involving impaction movement of more than 2 mm, occlusal plane canting of more than 3°, or midline discrepancies of more than 2.5 mm. Other cases were simple cases. Enrolled patients were randomly allocated into the digital occlusal splint (DOS) cohort and the digital templates (DT) cohort. The outcome variable was surgical accuracy, defined as the average deviation between the planned and postsurgical locations of bilateral maxillary central incisors, canines, first premolars, and first molars. Predictor variables were 1) operative complexity, simple versus complicated; and 2) technique for positioning the maxilla, DOS versus DT. Covariates were age and planned surgical movement. Two-way analysis of variance was used. RESULTS: Seventy patients were included in this study. Thirty-three were in the DOS cohort, and 37 in the DT cohort. The average deviation was significantly smaller in the complicated cases in the DT cohort (1.37 mm; 95% confidence interval, 1.08-1.66 mm) than that in the DOS cohort (2.47 mm; 95% confidence interval, 1.92-3.02 mm) (P = .002). The deviations in anteroposterior direction of complicated cases in the DT cohort were smaller than the corresponding values of the DOS cohort (P = .035). There is no significant difference between the deviation values of simple and complicated cases using templates (P = .116). CONCLUSION: These results indicate that in complicated cases, printed guiding templates exhibit better accuracy for repositioning the maxilla than printed occlusal splints, and the effect of templates in different cases proved to be stable.

Association of MDR1 C1236T Polymorphisms and B Cell Non-Hodgkin Lymphoma.

Background: Multidrug resistance gene 1 (MDR-1) encodes for P-glycoprotein (P-gp) recognized for removing cytostatic drugs from tumor cells. MDR1 gene polymorphisms change function of P-gp. In this study, we are interested in investigating whether MDR1 C1236T single nucleotide polymorphisms (SNPs) affect the susceptibility and treatment-related toxicities in B-cell non-Hodgkin lymphoma (B-NHL) in the population of eastern China. Materials and methods: A group of 107 B-NHL patients and 150 healthy donors, unrelated ethnic Han Chinese and residents of eastern China, were included in this study. The MDR1 C1236T polymorphisms were determined using polymerase chain reaction-allele specific primers after extraction of genomic DNA. Analyses were performed using SPSS and Arlequin software. Results: MDR1 C1236T polymorphisms were not significantly related to the risk and treatment-related toxicities of B-NHL. A significant association between extranodal sites and C1236T allele was observed (C vs T: P=0.01). Conclusion: Our findings could expand our understanding of MDR1 in B-NHL and provide references for further research in multidrug resistance.