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The lateral poststyloid space (LPSS) located at the posterolateral aspect of the styloid process. This study aims to explore the anatomical relationships in LPSS via a transoral corridor, providing reference for addressing lesions extending to this region. An endoscopic transoral approach for exposure of the LPSS was performed on 6 cadaveric specimens (12 sides). Related landmarks were explored, and transoral extirpation of tumors extended into LPSS was employed in 12 patients. The deep lobe of the parotid gland, extratemporal facial nerve, and the accompanying artery in the LPSS were sufficiently exposed via the transoral corridor in all 12 cadaveric sides. The transoral corridor provided adequate exposure for tumors extending to the LPSS, and en bloc resection was achieved in these 12 patients. No facial nerve or vascular injury occurred, and no recurrence observed in this cohort with an average follow-up of 26 months. An endoscopic transoral approach provides a direct access to the LPSS. Appreciation of the anatomical relationships within the LPSS is valuable for employing a transoral extirpation of tumors extending to this specific region.

Aim To explore the prevalence of nurse‐patient disputes and the influencing factors based on an analysis of patient characteristics. Design A cross‐sectional study. Methods This study used the convenience sampling method. Three self‐designed questionnaires based on clinical experience and literature review were used to collect the current status of nurse‐patient disputes and to assess patients’ humanistic qualities and patients’ recognition of nursing work. The Big Five personality questionnaire was used to assess the five personality traits of patients. Results Of the patients, 9.6% reported having a dispute with nurses. The results of binary logistic regression analysis indicated that patients’ humanistic quality, recognition of nursing work and agreeableness in personality traits had a negative predictive effect on nurse‐patient disputes, while family monthly income and neuroticism in personality traits positively predicted disputes.

Hippocampus is an important anatomical region for Alzheimer's Disease (AD) identification. In this paper, a multi-scale attention-based convolutional network is proposed for AD identification. The two dimensional (2D) images in three different planes of hippocampal subfields are used as input of three branches of the proposed network, which achieves effective extraction of three dimensional (3D) data features while reducing the network complexity and improving the computational efficiency. The end-to-end 2D multi-scale attention-based deep learning network improves the diversity of the extracted features and captures significance of various voxels for classification, which achieves significant classification performance without handcrafted feature extraction and model stacking. Experimental results illustrate the effectiveness of the proposed method on AD identification. The proposed method will be useful for further medical analysis on hippocampal subfields of the brain for diagnosis of neurodegenerative disease.

Aim To identify the symptom clusters of early‐stage poststroke depression (PSD) and provide an in‐depth understanding of the symptoms. Design A mixed‐methods study with a convenient sampling method was used. Methods A cross‐sectional questionnaire survey in 231 stroke patients and semi‐structured interviews in 14 stroke patients were conducted in the neurological department of a comprehensive hospital in Southeast China. Data from the questionnaire survey were analysed through descriptive and exploratory factor analyses; data from the semi‐structured interview were transcribed verbatim and analysed through inductive content analysis. This study adheres to the GRAMMS checklist. Results Exploratory factor analysis revealed six symptom clusters of early‐stage PSD that accounted for an ideal variance in PSD: nervous, wakefulness, emotional, dull, guilt and low mood. Further, inductive content analysis revealed five themes that were like the above symptom clusters, except for the dull symptom cluster.

A trans-lateral oropharyngeal wall approach (TLOWA) to the petrous apex has not been previously defined. This study aims to assess the feasibility of a TLOWA for surgical access to the petrous apex and the petroclival region.An endoscopic TLOWA for exposure of the petrous apex and petroclival region was performed on five cadaveric specimens (10 sides). Associated anatomical landmarks were defined, and the strategies for maximal exposure of the internal carotid artery (ICA) were explored.Via a TLOWA, the parapharyngeal ICA was widely exposed in all 10 sides. Following transection of the Eustachian tube, the inferior petrous apex and petroclival region could be sufficiently exposed. After drilling the anteroinferior bony canal, the horizontal petrous ICA, foramen lacerum, and the paraclival ICA could be adequately revealed.The TLOWA may provide an alternative corridor for access to the petrous apex and the petroclival region. The parapharyngeal, petrous, lower paraclival ICAs, and the foramen lacerum could be adequately exposed via the TLOWA.

Performing a nasopharyngectomy via a transoral approach has been reported; however, defining landmarks to facilitate this approach has not been addressed. This study aims to explore anatomical landmarks to aid in performing a nasopharyngectomy via the transoral corridor.An endoscopic transoral nasopharyngectomy was performed on six cadaveric specimens (12 sides). Related anatomical landmarks were defined, and the strategy to preserve the parapharyngeal internal carotid artery (pICA) was explored.An endoscopic transoral nasopharyngectomy was successfully achieved in all 12 sides. Utilizing the pterygoid hamulus as a landmark, the cartilaginous ET and attachments could be adequately exposed. Identification of the pICA is a prerequisite prior to Eustachian tube (ET) transection. The sphenoidal spine and the petrotympanic fissure could be sufficiently revealed in all 12 sides, which aided in transection of the cartilaginous ET without pICA injury. The ET and the prevertebral contents could be adequately removed via the transoral corridor.The pterygoid hamulus, sphenoidal spine and petrotympanic fissure serve as reliable landmarks for performing a transoral nasopharyngectomy. Identification of the pICA is a prerequisite prior to transection of the ET to avoid pICA injury.

BackgroundTo identify gender differences in factors associated with the health literacy of hospitalized older patients with chronic diseases.MethodsA total of 471 hospitalized older patients with chronic diseases in four hospitals were investigated from May 2019 to June 2020. The self-developed demographic information questionnaire, the “Health Literacy Scale for Patients with Chronic Diseases” and the “Self-Efficacy for Managing Chronic Diseases 6-item Scale” were applied in this study. Multiple linear regression was used to assess the factors influencing health literacy among older patients with chronic diseases by gender.ResultsThe factors influencing health literacy differed by gender. Male health literacy was related to education background, number of children, monthly income, duration of chronic disease and chronic disease self-efficacy. For females, health literacy was associated with age, education background, monthly income, duration of chronic disease and chronic disease treatment.ConclusionHealthcare providers should focus on the above-mentioned factors that could help identify those with low health literacy differ base on gender. Gender-specific strategies should be developed to improve the health literacy of older patients with chronic diseases and strengthen their chronic disease management.

BackgroundRestraint is widely used in nursing homes to address safety concerns. However, many studies have shown that improper restraint can lead to many adverse outcomes. Nursing staff are the main practitioners of physical restraint in nursing homes and play an important role in restraint decision-making and management. In China, there is still a lack of large-scale surveys on the current situation regarding the use of restraint. This study aimed to identify this situation and the influencing factors of the knowledge, attitude, and practice of nursing staff regarding physical restraint in elderly care institutions.MethodsA cross-sectional multicenter descriptive study was conducted. A total of 311 staff in 25 elderly care institutions in Zhejiang Province were recruited using a quota sampling method. A homemade questionnaire was administered to collect general information and information on knowledge, attitude and practice regarding physical restraint.ResultsThe average scoring rates of the knowledge and attitude dimensions of the 311 staff were 48.7 and 75.6%, respectively. The average scoring rate of the practice dimension of 140 staff who implemented restraint was 80.1%. Educational background and training experience were the influencing factors of restraint knowledge. Training experience, educational background and professional title were the influencing factors of restraint attitude. Restraint knowledge and length of service were the influencing factors of restraint practice.ConclusionsKnowledge of physical restraint among nursing staff is not promising. Their attitude toward restraint was inappropriate or irresponsible in some aspects. Restraint practice is not sufficiently standardized. It is necessary to strengthen restraint training for nursing staff to improve their overall level of restraint knowledge, attitude and practice.

Melanoma is an immunogenic cancer with a high response rate to immune checkpoint inhibitors (ICIs). It harbors a high mutation burden compared with other cancers and, as a result, has abundant tumor-infiltrating lymphocytes (TILs) within its microenvironment. However, understanding the complex interplay between the stroma, tumor cells, and distinct TIL subsets remains a substantial challenge in immune oncology. To properly study this interplay, quantifying spatial relationships of multiple cell types within the tumor microenvironment is crucial. To address this, we used cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) to simultaneously quantify the expression of 35 protein markers, characterizing the microenvironment of 5 benign nevi and 67 melanomas. We profiled more than 220,000 individual cells to identify melanoma, lymphocyte subsets, macrophage/monocyte, and stromal cell populations, allowing for in-depth spatial quantification of the melanoma microenvironment. We found that within pretreatment melanomas, the abundance of proliferating antigen-experienced cytotoxic T cells (CD8 + CD45RO + Ki67 + ) and the proximity of antigen-experienced cytotoxic T cells to melanoma cells were associated with positive response to ICIs. Our study highlights the potential of multiplexed single-cell technology to quantify spatial cell-cell interactions within the tumor microenvironment to understand immune therapy responses.

Aims and objectives This study aimed to obtain the incidence of diastasis recti abdominis (DRA) and analyse possible risk factors in adult females. Moreover, the relationships between DRA and lower back pain, pelvic floor function and quality of life were also analysed. Background Diastasis recti abdominis is a separation of the abdominal muscles at the linea alba. Currently, studies on the prevalence rates, risk factors and consequences of DRA are varied. In particular, reports on DRA among adult women are lacking. Design A one-sample questionnaire study design is used following the STROBE checklist. Methods The inter-rectus distance was measured by computed tomography in 644 women. Custom questionnaires, the Oswestry Disability Index, The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were used to investigate personal information, the subjects' back pain, pelvic floor function and quality of life, respectively. Results The incidence of DRA was 28.4%. Age, the number of pregnancies, BMI and diabetes were influencing factors for DRA. After age stratification, pregnancy and diabetes were found to be risk factors for DRA in young women, and obesity and diabetes were risk factors for DRA in older women. This study showed that the association between DRA and low back pain was highly significant. Conclusions Diastasis recti abdominis is common in adult women. Avoiding multiple pregnancies, preventing diabetes and controlling weight may prevent DRA, which may be beneficial for decreasing low back pain in women. Relevance to clinical practice The findings have important implications for the health of adult women which can provide the basis for appropriate nursing implementation for DRA patients. The application of specific prevention and intervention measures for the risk factors may reduce the severity of low back pain.

Background and aims Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown. Approach and results We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury. Conclusions Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.

Objective. Stromal cells and immune cells have important clinical significance in the microenvironment of colorectal cancer (CRC). This study is aimed at developing a CRC gene signature on the basis of stromal and immune scores. Methods. A cohort of CRC patients (n=433) were adopted from The Cancer Genome Atlas (TCGA) database. Stromal/immune scores were calculated by the ESTIMATE algorithm. Correlation between prognosis/clinical characteristics and stromal/immune scores was assessed. Differentially expressed stromal and immune genes were identified. Their potential functions were annotated by functional enrichment analysis. Cox regression analysis was used to develop an eight-gene risk score model. Its predictive efficacies for 3 years, 5 years, overall survival (OS), and progression-free survival interval (PFI) were evaluated using time-dependent receiver operating characteristic (ROC) curves. The correlation between the risk score and the infiltering levels of six immune cells was analyzed using TIMER. The risk score was validated using an independent dataset. Results. Immune score was in a significant association with prognosis and clinical characteristics of CRC. 736 upregulated and two downregulated stromal and immune genes were identified, which were mainly enriched into immune-related biological processes and pathways. An-eight gene prognostic risk score model was conducted, consisting of CCL22, CD36, CPA3, CPT1C, KCNE4, NFATC1, RASGRP2, and SLC2A3. High risk score indicated a poor prognosis of patients. The area under the ROC curves (AUC) s of the model for 3 years, 5 years, OS, and PFI were 0.71, 0.70, 0.73, and 0.66, respectively. Thus, the model possessed well performance for prediction of patients’ prognosis, which was confirmed by an external dataset. Moreover, the risk score was significantly correlated with immune cell infiltration. Conclusion. Our study conducted an immune-related prognostic risk score model, which could provide novel targets for immunotherapy of CRC.

Decorating the membrane surface of vesicle carriers with proteins for targeted delivery has been achieved mainly by chemical methods. In this study, we report the rational design of a lipid-mimicking peptide for biomembrane decoration without chemical conjugation. A peptide Pm45 consisting of a hydrophobic helical tail and an anionic headgroup linked with an integrin-targeting RGD moiety was manually designed. Pm45 was synthesized and characterized, which confirmed an alpha-helix at the C-terminal. Pm45 spontaneously intercalated into the lipid bilayer as illustrated by quartz crystal of microbalance with dissipation (QCM-D), a calcein leakage assay, and TEM. The intercalation was accomplished within 10 min, and the ITC results indicated that the affinity of Pm45 binding with lipids was ~100-fold greater than that of the naturally occurring cell-penetrating peptide Ib-AMP4. In vitro cellular experiments indicated that the Pm45-decorated erythrocyte vesicles specifically bound and killed integrin αvβ3-expressing MDA-MB-231 breast cancer cells. The targeting potential of Pm45-decorated erythrocyte vesicles was further evaluated in an MDA-MB-231 xenograft nude mouse model. The in vivo therapeutic effects indicated that the targeting vesicles significantly improved the therapeutic effect of encapsulated doxorubicin (DOX) compared with that of DOX or non-targeting vesicles. NIRF imaging implied that the targeting vesicles improved the pharmacokinetics of DOX in vivo and concentrated DOX in the tumour tissue at levels >50% higher than those achieved by non-targeting liposomes. This study reports a new method for liposome decoration as an alternative to chemical conjugation.

Transnasal exposure of the jugular foramen region (JFR) often requires transection of the Eustachian tube (ET). This study aims to propose a transoral corridor for access to the JFR with preservation of the ET.Cadaveric dissection and case illustration.An endoscopic transoral approach for exposure of the JFR was performed on 5 cadaveric specimens (10 sides). Six patients who underwent a transoral resection of schwannoma within the JFR were retrospectively analyzed.Direct exposure of the JFR with a 0° scope via a transoral approach was feasible, and the internal carotid artery and lower cranial nerves could be adequately exposed, and preservation of the ET was achieved in all 10 sides of the cadaveric specimens. For six patients with JFR tumors, the transoral approach provided adequate access to achieve a gross total resection with ET preservation. Intraoperative cerebral spinal fluid (CSF) leak was encountered in one patient, and a multilayer reconstruction was employed for reconstruction. No operative field or intracranial infection, persistent CSF leak, or emergent airway issues occurred. No recurrence occurred in this cohort with an average follow-up of 12 months.The transoral approach provided a reliable corridor for access into the JFR with preservation of the ET. For select lesions with expansion into the posterior cranial fossa, a transoral corridor may serve as an alternative for tumor extirpation.4 Laryngoscope, 132:1374-1380, 2022.

Early detection of the pulmonary nodule from physical examination low-dose computer tomography (LDCT) images is an effective measure to reduce the mortality rate of lung cancer. Although there are many computer aided diagnosis (CAD) methods used for detecting pulmonary nodules, there are few CAD systems for small pulmonary nodule detection with a large amount of physical examination LDCT images.In this work, we designed a CAD system called Pulmonary Nodules Detection Assistant Platform for early pulmonary nodules detection and classification based on the physical examination LDCT images. Based on the preprocessed physical examination CT images, the three-dimensional (3D) CNN-based model is presented to detect candidate pulmonary nodules and output detection results with quantitative parameters, the 3D ResNet is used to classify the detected nodules into intrapulmonary nodules and pleural nodules to reduce the physician workloads, and the Fully Connected Neural Network (FCNN) is used to classify ground-glass opacity (GGO) nodules and non-GGO nodules to help doctor pay more attention to those suspected early lung cancer nodules.Experiments are performed on our 1000 samples of physical examinations (LNPE1000) with an average diameter of 5.3 mm and LUNA16 dataset with an average diameter of 8.31 mm, which show that the designed CAD system is automatic and efficient for detecting smaller and larger nodules from different datasets, especially for the detection of smaller nodules with diameter between 3 mm and 6 mm in physical examinations. The accuracy of pulmonary nodule detection reaches 0.879 with an average of 1 false positive per CT in LNPE1000 dataset, which is comparable to the experienced physicians. The classification accuracy reaches 0.911 between intrapulmonary and pleural nodules, and 0.950 between GGO and non-GGO nodules, respectively.Experimental results show that the proposed pulmonary nodule detection model is robust for different datasets, which can successfully detect smaller and larger nodules in CT images obtained by physical examination. The interactive platform of the designed CAD system has been on trial in a hospital by combining with manual reading, which helps doctors analyze clinical data dynamically and improves the nodule detection efficiency in physical examination applications.

Antimicrobial peptides (AMPs) are typical cell penetrating peptides (CPPs) that intercalate into biomembranes and exhibit broad activities. We designed a triple fusion protein consisting of an AMP, Ib-AMP4 at the N-terminus, a fluorescent GFP probe in the center, and the tumor-targeting peptide P1c at the other terminus. After purification from E. coli, the interaction between the Ib-AMP4-GFP-P1c fusion protein (IGP) and the lipid membrane was characterized. Experiments using isothermal titration calorimetry (ITC) and quartz crystal microbalance with dissipation (QCM-D) demonstrated that IGP proteins spontaneously bound the lipid bilayer with a maximal molar ratio of 1:52 (protein:lipid). Furthermore, transmission electron microscopy (TEM) confirmed that the IGP protein was present in the liposome membrane. After decoration with IGP proteins, the DOPC:DOPG liposomes were applied to cancer cells. Microscopy and flow cytometry reveal that the decorated liposomes selectively bound integrin αvβ3-positive A549 cells. In addition, compared with the common chemical conjugation method, the reported method seemed to be superior in certain aspects, such as simple sample preparation and cost-effectiveness. Next, the IGP protein was applied to decorate red blood cell (RBC) liposomes for targeted delivery in both in vitro and in vivo applications. The IGP-decorated RBC liposomes preferentially targeted integrin αvβ3 expressing A549 cancer cells. The in vivo imaging showed that IGP-decorated RBC liposomes were concentrated in tumor tissue and were primarily metabolized by the liver and kidney.

In this report, we described a large Han-Chinese family which presents with various phenotypes from unaffected to manifested nystagmus in females. Infantile nystagmus (IN) is characterized by bilateral, involuntary, and periodic eyeball oscillation, occurring at birth or within the first 6 months. The most common inheritance pattern of IN is an X-linked form with incomplete penetrance among females, and the FERM domain containing 7 gene (FRMD7) is a main disease-causing gene. A combination of exome sequencing and Sanger sequencing, as well as detailed clinical examinations were performed on the Chinese IN family. An FRMD7 c.47T>C (p.Phe16Ser) variant was proposed as the disease-causing variant. Incomplete penetrance was found in females with the FRMD7 c.47T>C variant, and hemizygous male affected subjects presented more severe manifestations compared to heterozygous female affected subjects. These findings could enhance genetic counseling and antenatal diagnosis of IN.

Background Haemophilia A (HA), inherited via an X-linked recessive pattern, is the most common severe lifelong bleeding disorder caused by mutations in the coagulation factor VIII gene (F8). It has significant socio-economic effects due to its long course of disease and high cost of care. These impacts argue for a more accurate genetic diagnosis in an increasingly complex clinical environment. Methods A three-generation Han-Chinese family with mild HA was recruited in the study. Exome sequencing was performed in the index case to detect potential disease-causing mutations, and Sanger sequencing was applied to verify the mutation in the family. Results A hemizygous c.602G > A variant in the F8 gene, leading to a single amino acid substitution at codon 201 from glycine to glutamic acid (p.G201E) within the factor VIII (FVIII) A1 domain, was identified in the HA family. This mutation detected in the proband was found in his affected sibling, while it was absent in the unaffected family member and the two hundred ethnically-matched controls. The mutation affects an evolutionary conserved residue, which may impact the tertiary structure of FVIII. Conclusion The study findings should provide for more dependable and precise genetic counseling which may assist in perfecting family management.

Aim This study aimed to describe levels of social support and explore the factors predictive of social support for Chinese family caregivers of patients with dementia. Background Social support levels and their predictive factors in Chinese dementia caregivers have not been well documented, which need to be further clarified to provide a basis for creating effective social support strategies. Methods This was a cross-sectional study with 91 participants who completed a demographic questionnaire and the Social Support Rating Scale from 2015 to 2016. Results Chinese family caregivers of patients with dementia received moderate social support. Caregivers' subjective support domain scores and support utilization domain scores were significantly lower than those of the normal Chinese population, whereas caregivers' total social support scores were higher than those of the normal Chinese population. Family caregivers' monthly household income, educational level and place of residence were predictors of their own social support. Conclusion Social support in Chinese caregivers of patients with dementia needs to be improved, especially the subjective support and support utilization. Healthcare professionals should pay special attention to caregivers with a lower monthly household income and educational level and caregivers who lived in the suburban area. Summary statement What is already known about this topic? Social support is important for family caregivers of patients with dementia. Social support levels and their predictive factors in Chinese dementia caregivers have not been well documented. What this paper adds? Caregivers' subjective support and support utilization were significantly lower than the normal Chinese population; caregivers' total social support was significantly higher than the normal Chinese population. The best predictors of caregivers' social support were the monthly household income, educational level and place of residence of the caregivers. The implications of this paper: Healthcare professionals should pay special attention to caregivers with a lower monthly household income and educational level and caregivers who lived in the suburban area. Future research is needed to create effective nursing regimes, paying attention to caregivers with a lower educational level and caregivers who lived in the suburban area.

Background Brachiocephalic vein aneurysm is a rare vascular malformation, which is often reported in case reports. At present it has attracted much attention due to the serious complications, such as vein aneurysm rupture, pulmonary embolism, venous thrombosis, etc. We report a case of left brachiocephalic vein aneurysm with compression symptoms. Case presentation a 52-year-old male who was admitted to our hospital with irritating cough for more than 1 month. Chest contrast-enhanced CT showed a localized expansion of 5.2 cm in diameter of the left brachiocephalic vein in the anterior mediastinum. The patient received venous angioplasty with brachiocephalic vein aneurysm resection, and the postoperative recovery was well. Conclusion Surgical operation is an effecive treatment method for brachiocephalic vein aneurysm, but it is still necessary to choose the appropriate way according to the type, size, location, lesion scope and complications of the vein aneurysm.

Heterotaxy (HTX), a condition characterized by internal organs not being arranged as expected relative to each other and to the left-right axis, is often accompanied with congenital heart disease (CHD). The purpose was to detect the pathogenic variants in a Chinese family with HTX and CHD. A non-consanguineous Han Chinese family with HTX and CHD, and 200 unrelated healthy subjects were enlisted. Exome sequencing and Sanger sequencing were applied to identify the genetic basis of the HTX family. Compound heterozygous variants, c.3426-1G>A and c.4306C>T (p.(Arg1436Trp)), in the dynein axonemal heavy chain 11 gene (DNAH11) were identified in the proband via exome sequencing and further confirmed by Sanger sequencing. Neither c.3426-1G>A nor c.4306C>T variant in the DNAH11 gene was detected in 200 healthy controls. The DNAH11 c.3426-1G>A variant was predicted as altering the acceptor splice site and most likely affecting splicing. The DNAH11 c.4306C>T variant was predicted to be damaging, which may reduce the phenotype severity. The compound heterozygous variants, c.3426-1G>A and c.4306C>T, in the DNAH11 gene might be the pathogenic alterations resulting in HTX and CHD in this family. These findings broaden the variant spectrum of the DNAH11 gene and increase knowledge used in genetic counseling for the HTX family.

Retinitis pigmentosa (RP) is a severe hereditary retinal disorder characterized by progressive degeneration of rod and cone photoreceptors. This study identified a novel frameshift mutation, c.385delC, p.(L129WfsTer148), in the cyclic nucleotide-gated channel beta 1 (CNGB1) gene of a consanguineous Han Chinese family with autosomal recessive RP (arRP). This expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling.The present study sought to identify potential pathogenetic gene mutations in a five-generation consanguineous Han Chinese family with RP.Two members of a five-generation consanguineous Han Chinese pedigree with arRP and 100 normal individuals were enrolled in this study. Exome sequencing was performed on the 70-year-old male proband from a consanguineous family to screen potential pathogenic mutations according to the American College of Medical Genetics and Genomics for the interpretation of sequence variants. Sanger sequencing was performed on the proband, the proband's unaffected son, and 100 normal individuals to verify the disease-causing mutation.A novel frameshift mutation, c.385delC, p.(L129WfsTer148), with homozygous status in the CNGB1 gene was identified in the proband of the family with arRP, and the mutation with heterozygous status was carried by the asymptomatic son.The c.385delC (p.(L129WfsTer148)) mutation in the CNGB1 gene screened by exome sequencing is probably responsible for the RP phenotype in this family. The result expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling.

Familial amyloid polyneuropathies (FAPs) are life-threatening, autosomal dominant diseases resulting, in most instances, from transthyretin gene (TTR) variants. A small number of TTR variants lead to leptomeningeal amyloidosis (LA), which is a rare FAP subtype with late-onset central nervous system (CNS) impairment symptoms. Previous studies suggest that LA's CNS selectivity was due to complete endoplasmic reticulum-associated degradation of highly destabilized mutants in peripheral tissues. LA's later age at onset (AAO) was due to lower choroid plexus secretory efficacy. This study reports on a family with LA, including six symptomatic and three presymptomatic members. The LA diagnosis was confirmed by leptomeningeal enhancement on contrast MRI, elevated cerebrospinal fluid protein levels, and positive Congo red staining. The predominant symptoms included headaches, dizziness, vomiting, hallucinations, and cognitive impairments which associated with obstructive hydrocephalus. The TTR p.D38G variant with the lowest secretory efficacy was identified as the genetic cause by whole exome sequencing. The family had a statistically significantly earlier mean AAO of 31.3 ± 7.4 (p = 0.001). These uncommon phenotypes indicate unknown factors influencing the progress of CNS impairment via TTR mutants. Medical imaging examinations suggest the potential early diagnosis value of contrast MRI and the importance of ependyma involvement in LA. LA genetic and clinical data were reviewed and summarized. These findings expand the FAPs' phenotypic spectrum and are valuable in FAP diagnosis, treatment, and further research.

GNE myopathy is a rare, recessively inherited, early adult‐onset myopathy, characterized by distal and proximal muscle degeneration which often spares the quadriceps. It is caused by mutations in the UDP‐N‐acetylglucosamine 2‐epimerase/N‐acetylmannosamine kinase gene (GNE). This study aimed to identify the disease‐causing mutation in a three‐generation Han‐Chinese family with members who have been diagnosed with myopathy. A homozygous missense mutation, c.1627G>A (p.V543M) in the GNE gene co‐segregates with the myopathy present in this family. A GNE myopathy diagnosis is evidenced by characteristic clinical manifestations, rimmed vacuoles in muscle biopsies and the presence of biallelic GNE mutations. This finding broadens the GNE gene mutation spectrum and extends the GNE myopathy phenotype spectrum.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder primarily characterized by multiple cafe-au-lait macules, peripheral neurofibromas, skinfold freckling, and Lisch nodules. The causative genetic factor is the neurofibromin 1 gene (NF1), which encodes a Ras GTPase-activating protein called neurofibromin. NF1 variants may lead to loss of neurofibromin function and activation of downstream cell growth. This study aims to discover the disease-causing variants responsible for NF1 in two Han Chinese families by using exome sequencing combined with Sanger sequencing. A recurrent missense variant c.269T>C (p.Leu90Pro) and a novel nonsense variant c.2993dupA (p.Tyr998*) in the NF1 gene were identified. These variants co-segregated with the disorder in the pedigrees and were absent in the normal controls. The results broaden the NF1 mutation spectrum responsible for NF1. This may be helpful in genetic counseling, clinical management, and gene-targeted therapies for NF1.

Background/Aims: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis. It is characterized by diffuse yellow keratoses on the palmoplantar epidermis, with an erythematous border. The keratin 9 gene (KRT9) and less frequently the keratin 1 gene (KRT1) are responsible for EPPK. This study aims to identify and analyse genetic defects responsible for EPPK in a Han Chinese pedigree. Methods: A four-generation Han Chinese pedigree containing five individuals affected with EPPK was recruited. Exome sequencing, Sanger sequencing, and bioinformatics tools were conducted to identify the mutation in this pedigree. HaCaT cells were transfected with either wild-type or mutated KRT9. Confocal laser immunofluorescence assay, imaging processing, and statistical analysis were performed to evaluate wild-type and mutant KRT9 groups. Results: A novel heterozygous c.1369C>T transition (p.Leu457Phe) in exon 6 of the KRT9 gene was identified in four patients. It co-segregated with the disorder in the family. Functional analysis showed that withdrawal of the filament network from the cell periphery and particle formation were present in about 10% of Leu457Phe-transfected HaCaT cells, while approximately 3% of cells transfected with wild-type KRT9 showed this phenotype. The particles in mutant group were larger than that in wild-type group (P-value < 0.05). Conclusion: The variant may be the disease-causing missense mutation and produce dominant negative effects by interrupting keratin network formation. This study indicates the pathogenic role of the KRT9 gene mutation in this pedigree with EPPK, and may be helpful in genetic counseling, prenatal diagnosis and gene-targeted therapies of EPPK.

Background This presentation of two cases and literature review discusses the epidemiology, clinical manifestations, pathogenesis, diagnosis, treatment, and prognosis of high-grade glioma with extracranial metastases. Methods A retrospective analysis of the clinical features of two cases of malignant glioma, including metastatic sites, pathological data, and treatment methods, and a literature review was performed. Results Two patients developed extracranial metastases within 1 year after surgery for primary glioma. One patient developed cervical lymph node and bone metastases while the other developed bone metastases, and both patients died within 2 months after the diagnosis of the extracranial metastasis. Conclusion Extracranial metastases may develop from malignant gliomas. According to the literature, the most common extracranial site is intraspinal (along the neural axis), followed by the vertebrae, lungs, liver, and lymph nodes. The complex metastatic mechanism remains unclear, and the prognosis is very poor, with a survival duration of less than 6 months.

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive visual loss and night blindness due to retinitis pigmentosa (RP), with or without vestibular dysfunction. The purpose of this study was to detect the causative gene in a consanguineous Chinese family with USH. A c.3696_3706del (p.R1232Sfs*72) variant in the myosin VIIa gene (MYO7A) was identified in the homozygous state by exome sequencing. The co‑segregation of the MYO7A c.3696_3706del variant with the phenotype of deafness and progressive visual loss in the USH family was confirmed by Sanger sequencing. The variant was absent in 200 healthy controls. Therefore, the c.3696_3706del variant may disrupt the interaction between myosin VIIa and other USH1 proteins, and impair melanosome transport in retinal pigment epithelial cells. Notably, bilateral auditory brainstem responses were absent in two patients of the USH family, while distortion product otoacoustic emissions were elicited in the right ears of the two patients, consistent with clinical diagnosis of unilateral auditory neuropathy spectrum disorder. These data suggested that the homozygous c.3696_3706del variant in the MYO7A gene may be the disease‑causing mutation for the disorder in this family. These findings broaden the phenotype spectrum of the MYO7A gene, and may facilitate understanding of the molecular pathogenesis of the disease, and genetic counseling for the family.

Muscular dystrophy‐dystroglycanopathy (MDDG) is a genetically and clinically heterogeneous group of muscular disorders, characterized by congenital muscular dystrophy or later‐onset limb‐girdle muscular dystrophy accompanied by brain and ocular abnormalities, resulting from aberrant alpha‐dystroglycan glycosylation. Exome sequencing and Sanger sequencing were performed on a six‐generation consanguineous Han Chinese family, members of which had autosomal recessive MDDG. Compound heterozygous mutations, c.1338+1G>A (p.H415Kfs*3) and c.1457G>C (p.W486S, rs746849558), in the protein O‐mannosyltransferase 1 gene (POMT1), were identified as the genetic cause. Patients that exhibited milder MDDG manifested as later‐onset progressive proximal pelvic, shoulder girdle and limb muscle weakness, joint contractures, mental retardation and elevated creatine kinase, without structural brain or ocular abnormalities, were further genetically diagnosed as MDDGC1. The POMT1 gene splice‐site mutation (c.1338+1G>A) which leads to exon 13 skipping and results in a truncated protein may contribute to a severe phenotype, while the allelic missense mutation (p.W486S) may reduce MDDG severity. These findings may expand phenotype and mutation spectrum of the POMT1 gene. Clinical diagnosis supplemented with molecular screening may result in more accurate diagnoses of, prognoses for, and improved genetic counselling for this disease.

Perinatal asphyxia remains a frequent cause of neonatal mortality and long-term neurodevelopmental sequelae, despite the introduction of therapeutic hypothermia. Specific maternal characteristics may predispose asphyxiated newborns treated with hypothermia to worse outcome.To investigate the possible association between specific maternal factors and adverse outcome in asphyxiated newborns treated with hypothermia.We conducted a retrospective review of our database of 215 asphyxiated newborns treated with hypothermia from 2008 to 2015. We collected maternal characteristics including parity and labor duration, and we definedAsphyxiated newborns born to nulliparous mothers had a significantly higher risk of adverse outcome (61%), compared to asphyxiated newborns born from primiparous (19%) and multiparous (20%) mothers (Newborns with evidence of perinatal asphyxia, born to nulliparous mothers, and especially to those in whom the duration of labor has been prolonged, might be at higher risk of death or brain injury despite the use of therapeutic hypothermia.

Aim: Diabetic wound healing is seriously interrupted, and administration of KGF for wound treatment is restricted by its inherent instability. We aim to develop an ideal way toward KGF stabilization, thus improving diabetic wound healing. Materials & methods: We conjugated KGF with gold nanoparticles (GNPs) and determined the stability and binding affinity. Biological effects of conjugates (KGF-GNPs) were evaluated in vitro and in an animal model. Results: KGF-GNPs revealed high stability under hostile circumstances because of the preserved secondary structure and possessed elevated binding affinity to KGF receptor. Moreover, application of KGF-GNPs contributed to accelerated wound recovery in diabetic rats, including re-epithelialization and contraction. Conclusion: KGF-GNPs were promising for future clinical application for diabetic wound therapy.

Background Ellis‐van Creveld syndrome (EVC), a very rare genetic skeletal dysplasia, is clinically characterized by a tetrad consisting of chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. The aim of this study was to identify the genetic defect for EVC in a five‐generation consanguineous Han‐Chinese pedigree. Methods A five‐generation, 12‐member Han‐Chinese pedigree was enrolled in this study. Exome sequencing was applied in the proband to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in family members and 200 unrelated ethnicity‐matched controls. Results A novel homozygous variant, c.2014C>T, p.(Q672*), in the EvC ciliary complex subunit 1 gene (EVC), was detected in the patient, which was cosegregated with the disease in the family and absent in the controls. Conclusion The identified novel homozygous EVC variant, c.2014C>T, p.(Q672*), was responsible for EVC in this Han‐Chinese pedigree. The findings in this study extend the EVC mutation spectrum and may provide new insights into EVC causation and diagnosis with implications for genetic counseling and clinical management.

Retinitis pigmentosa (RP), the most common type of inherited retinal degeneration causing blindness, initially manifests as severely impaired rod function followed by deteriorating cone function. Mutations in the rhodopsin gene (RHO) are the most common cause of autosomal dominant RP (adRP). The present study aims to identify the disease-causing mutation in a numerous, four-generation Han-Chinese family with adRP detected by whole exome sequencing and Sanger sequencing. Afflicted family members present classic adRP along with heterogeneous clinical phenotypes including differing refractive errors, cataracts, astigmatism and epiretinal membranes. A missense mutation, c.403C>T (p.R135W), in the RHO gene was identified in nine subjects and it co-segregated with family members. The mutation is predicted to be disease-causing and results in rhodopsin protein abnormalities. The present study extends the genotype–phenotype relationship between RHO gene mutations and adRP clinical findings. The results have implications for familial genetic counseling, clinical management and developing RP target gene therapy strategies.

Background:Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5).Objective:The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree.Methods:Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls.Results:Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls.Conclusion:By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

Breast cancer (BC) is the most common female cancer found worldwide. It is responsible for 25% of all cancer patients in females. Hereditary BC accounts for about 5–10% of all BC cases. The breast cancer 1 gene (BRCA1) and the breast cancer 2 gene (BRCA2) are the two most-studied BC susceptibility genes. Genetic testing for disease-causing mutations in BRCA1, BRCA2, and other BC susceptibility genes is strongly recommended for members of families having a BC family history. The present study found a heterozygous c.5722_5723del mutation in the BRCA2 exon 11 of a large Han-Chinese BC family using whole exome sequencing and Sanger sequencing. It may cause DNA double-strand breaks repair dysfunction by disturbing homologous recombination, further resulting in BC. The study findings may help supplement and further improve genetic testing strategies and BC risk estimation methodologies in China.

Background Osteogenesis imperfecta (OI), a genetically determined connective tissue disorder, is characterized by increased bone fragility and reduced bone mass. Clinical presentation severity ranges from very mild types with nearly no fractures to intrauterine fractures and perinatal lethality. It can be accompanied by blue sclerae, dentinogenesis imperfecta (DI), hearing loss, muscle weakness, ligament laxity, and skin fragility. This study sought to identify pathogenic gene variants in a four‐generation Han Chinese family with OI type I. Methods In order to unveil the molecular genetic factors underlying the disease phenotype, whole exome sequencing in a member, with OI type I, of a Han Chinese family from Hunan, China was performed. The variant identified by whole exome sequencing was further tested by Sanger sequencing in the family members. Results A heterozygous missense variant (NM_000089.3: c.3197G>T; NP_000080.2: p.Gly1066Val) in the collagen type I alpha 2 chain gene (COL1A2) was identified in four patients. It co‐segregated with the disease in the family. Conclusion The sequence variant may be a disease‐causing factor resulting in abnormal type I procollagen synthesis and leading to OI type I. This finding has significant implications for genetic counseling and clinical monitoring of high‐risk families and may be helpful for understanding pathogenic mechanism of OI and developing therapies.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant, inherited, systemic, vascular disorder primarily involving the small arteries. It is characterized by migraine, recurrent ischemic strokes, cognitive decline, and dementia. Mutations in the Notch receptor 3 gene (NOTCH3) and the HtrA serine peptidase 1 gene (HTRA1) are 2 genetic causes for CADASIL. The NOTCH3 gene, located on chromosome 19p13.12, is the most common disease-causing gene in CADASIL.To investigate genetic causes in 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL.Exome sequencing was performed on both patients and potential pathogenic mutations were validated by Sanger sequencing.This study reports on 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL, identifying that NOTCH3 mutations were the genetic cause. A common mutation, c.268CT (p.Arg90Cys), and a novel mutation, c.331GT (p.Gly111Cys) in the NOTCH3 gene, were detected and confirmed in the patients, respectively, and were predicted to be deleterious based on bioinformation analyses.We identified 2 NOTCH3 mutations as likely genetic causes for CADASIL in these 2 patients. Our findings broaden the mutational spectrum of the NOTCH3 gene accountable for CADASIL. Clinical manifestations supplemented with molecular genetic analyses are critical for accurate diagnosis, the provision of genetic counseling, and the development of therapies for CADASIL.

Objective To examine the distribution of brain metastases (BM) in relation to the hippocampus, so as to determine the risk of metastasis in the hippocampus, and thus provide experimental evidence for the hippocampal avoidance (HA) in patients with BM during radiotherapy. Methods (1) For the retrospective analysis of 116 patients diagnosed with malignancies, confirmed as BM, from December 2014 to December 2016 at the First Affiliated Hospital of Bengbu Medical College. We obtained the T1-weighted, postcontrast axial, sagittal, and coronal Magnetic Resonance imaging (MRI) images f the patients, in supine position, using the head restraints and head thermoplastic masks to adjust the positioning, with computed tomography (CT) positioning scan ranging from the head to the mandible (layer thickness: 3 mm). CT and MRI images were fused on a Philips Pinnacle v9.8 treatment planning system;(2) Every metastasis of the 565 metastases was contoured;(3) hippocampus were contoured, and hippocampus with 5 mm expansion envelopes were analyzed;(4) Using the SPSS 16.0 software, we analyzed the relation between the distribution and age, sex, Karnofsky performance status (KPS), primary site, aggregate volume of intracranial metastases and the whole brain. The data were analyzed using a binary logistic regression analysis method, with two-sided P 0.05). Conclusion This study showed a low risk for the perihippocampal metastases (PHM) and no significant correlation between PHM and age, sex, KPS, primary site, aggregate volume of intracranial metastases and the whole brain. Accordingly, it is may be acceptable to avoid the perihippocampal region during whole brain radiotherapy.

Probiotics are commensal or nonpathogenic microbes that confer beneficial effects on the host through several mechanisms such as competitive exclusion, antibacterial effects, and modulation of immune responses. Some probiotics have been found to regulate immune responses via immune regulatory mechanisms. T regulatory (Treg) cells, T helper cell balances, dendritic cells, macrophages, B cells, and natural killer (NK) cells can be considered as the most determinant dysregulated mediators in immunomodulatory status. Recently, fecal microbiota transplantation (FMT) has been defined as the transfer of distal gut microbial communities from a healthy individual to a patient’s intestinal tract to cure some immune disorders (mainly inflammatory bowel diseases). The aim of this review was followed through the recent literature survey on immunomodulatory effects and mechanisms of probiotics and FMT and also efficacy and safety of probiotics and FMT in clinical trials and applications.

Objective Thin basement membrane nephropathy (TBMN), an autosomal dominant inherited condition in general, is characterized clinically by persistent hematuria and pathologically by thinning of glomerular basement membrane. TBMN is occasionally accompanied with proteinuria, hypertension and renal impairment in some cases. The aim of this study is to explore the genetic defect in a Chinese pedigree with familial hematuria. Design and methods A four-generation Chinese Han pedigree with familial hematuria was recruited. Exome sequencing was conducted in the proband diagnosed as TBMN, followed by verification in the proband and other family members with Sanger sequencing. Results A novel missense variant, c.4616C > G (p.S1539C), in the fibronectin 1 gene (FN1), was identified, and it co-segregated with the disease condition in the family. It was not observed in 100 normal controls. Conclusions A missense variant in the FN1 gene is possibly responsible for familial hematuria or TBMN in this family, which may broaden the phenotype and mutation spectrums of the FN1 gene. A male patient in this family progressed to end-stage renal disease requiring kidney transplantation, supporting that familial hematuria or TBMN may not always be as benign as generally thought. The findings may have new implications for clinical monitoring and genetic counseling of the family, and may also help understand the pathogenesis.

Background & objectives: Alport syndrome (AS) is an inherited disorder characterized by glomerulonephritis and end-stage renal disease (ESRD). The aim of this study was to identify the gene responsible for the glomerulopathy in a Chinese family with autosomal dominant AS using exome sequencing. Methods: A 4-generation, 30-member Chinese Han family was enrolled in this study. Exome sequencing was conducted in the proband of the family, and then direct sequencing was performed in family members of the pedigree and 100 normal controls. Results: A novel frameshift mutation, c.3213delA (p.Gly1072GlufsFNx0169), in the collagen type IV alpha-4 gene (COL4A4) was found to be the genetic cause. Neither sensorineural hearing loss nor ocular abnormalities were present in the patients of this family. Other clinical features, such as age of onset, age of ESRD occurring and disease severity, varied among the patients of this family. Interpretation & conclusions: A novel frameshift mutation, c.3213delA (p.Gly1072GlufsFNx0169) in the COL4A4 gene, was identified in the Chinese pedigree with autosomal dominant AS. Our findings may provide new insights into the cause and diagnosis of AS and also have implications for genetic counselling.

Pseudopodium-enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, has been demonstrated to act as an oncogenic regulator in breast and pancreatic cancers. However, the role of PEAK1 in the progression and metastasis of lung cancer is still unknown. Here, we observed that ectopic PEAK1 expression promoted lung cancer cell migration and invasion, while PEAK1 knockout resulted in suppressed cell migration and invasion. Interestingly, cell proliferation did not significantly increase or decrease in either the PEAK1 overexpression or knockout groups compared with the corresponding control cells. In addition, PEAK1 overexpression could induce epithelial-to-mesenchymal transition (EMT) and the expression of matrix metalloproteinase-2 (MMP2) and MMP9 both in vitro and in vivo, whereas PEAK1 knockout had the opposite effects. Then, we had confirmed that PEAK1 was significantly upregulated in lung cancer tissues, and correlated with a higher tumor node metastasis stage. Moreover, PEAK1 upregulation markedly enhanced the activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and Janus kinase-2 (JAK2) signaling in lung cancer cells. Further work demonstrated that the combination of PD98059 with AZD1480 could reverse the effects of PEAK1-induced EMT, cell migration and invasion. Our findings highlight a newer mechanism for PEAK1 in regulating EMT and metastasis in lung cancer, which might serve as a therapeutic target for lung cancer patients.

Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family’s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.

The lack of standardized treatment is problematic in laser surgery for laryngeal cancer, and may result in an increased recurrence rate. This study analyzed the prognosis of early laryngeal carcinoma after different types of cordectomy with laser surgery.A cohort of 818 patients with stage Tis or T1 primary early glottic squamous cell carcinoma treated with COOf the 818 patients, According to the Kaplan-Meier method, the rate of 5-year overall survival was 92.8%, and the rates for 5-year disease-specific survival and 5-year locoregional control were 96.9% and 91.3%, respectively. Among the T1 patients, type II cordectomy with laser surgery had a significant impact on the 5-year locoregional control rate, but no obvious impact on the 5-year overall survival rate.There must be sufficient depth and extent of excision in T1 patientsand in early carcinoma especially those with possible microinvasive carcinoma.

Because of the exclusion for the patients more than 75 years (very elderly patients) in many clinical trials of esophageal cancer (EC), there is no consensus on prognosis and treatment for this population. We aim to evaluate the outcomes and aging‐related prognostic factors of definitive radiotherapy (RT) for very elderly EC patients. We retrospectively analyzed 149 very elderly EC patients consecutively treated between January 2015 and June 2016 by definitive intensity‐modulated radiotherapy (IMRT) with or without chemotherapy. The clinical outcome and toxicities were assessed, and the potential prognostic factors, such as nutritional risk index (NRI) and neutrophil–lymphocyte ratio (NLR), were analyzed statistically. The median follow‐up time for survivors was 22.5 months. The 2‐year overall survival (OS), local–regional failure‐free survival (LRFFS), and distant metastasis‐free survival (DMFS) were 51.6%, 54.7%, and 85.2%, respectively. Independent predictors for poorer OS were higher American Joint Committee on Cancer (AJCC) stage, lower NRI, and higher NLR value before RT. Meanwhile, the total dose (cutoff value 60 Gy) of planning gross tumor volume (PGTV) and chemotherapy was also identified as independent prognostic indicator for LRFFS and DMFS, respectively. 72 patients had treatment failure and 58 (80.6%), 6 (8.3%), and 18 (25.0%) patients had experienced local, regional, and distant failure, respectively. Few severe toxicities were observed. The conservative definitive RT with modern technique was effective for very elderly EC patients in short term with low rate and tolerable toxicities. Local residue or recurrence was the most common failure pattern. The aging‐related prognostic factors concerned nutrition and immune, such as NRI and NLR before RT, should be considered for use in future clinical practice.

MicroRNAs (miRs) have important roles in the pathogenesis of human malignancy. It has previously been suggested that deregulation of miR‑101 is associated with the progression of intrahepatic cholangiocarcinoma (ICC); however, the exact role of miR‑101 in the regulation of ICC metastasis remains largely unknown. The present study demonstrated that the expression levels of miR‑101 were significantly decreased in ICC tissue, as compared with matched adjacent normal tissue. Furthermore, miR‑101 was downregulated in the ICC‑9810 human ICC cell line, as compared with in the normal human intrahepatic biliary epithelial cell (HIBEC) line. Vascular endothelial growth factor (VEGF)‑C was identified as a target gene of miR‑101 in ICC‑9810 cells. The expression of VEGF‑C was negatively regulated by miR‑101 at the post‑transcriptional level in ICC‑9810 cells. Further investigation demonstrated that overexpression of miR‑101 markedly suppressed the migration and invasion of ICC‑9810 cells, and these effects were similar to those observed following VEGF‑C knockdown. Conversely, restoration of VEGF‑C reversed the inhibitory effects of miR‑101 overexpression on ICC‑9810 cell migration and invasion, thus suggesting that miR‑101 may suppress ICC‑9810 cell migration and invasion, at least partly via inhibition of VEGF‑C. It was also demonstrated that the mRNA and protein expression levels of VEGF‑C were frequently upregulated in ICC tissue and cells, and its expression level was inversely correlated with that of miR‑101 in ICC tissue. In conclusion, the present study identified important roles for miR‑101 and VEGF‑C in ICC, suggesting that miR‑101/VEGF‑C signaling may be a promising diagnostic and/or therapeutic target for ICC.

Intrahepatic cholangiocarcinoma (ICC) is the most common and deadly disease of the biliary tree due to its poor prognosis. Sal-like protein 4 (SALL4), a stem cell marker, has been identified as a potential target for aggressive hepatocellular carcinoma (HCC). In our study, 175 ICC cases with an average age of 55 years were included, and 53% (93/175) were male. And 28 adjacent non-tumor tissues were also collected. The SALL4-positive immunoreactivity was detected in a total of 102 ICC cases (58%), whereas all 28 adjacent tissues showed negative staining. Univariate analysis, showed that the SALL4-positive ICC cases had significantly more frequent lymph nodal metastasis (P = 0.0460), vascular invasion (P < 0.0001), and nerve invasion (P < 0.0001). Furthermore, the strong SALL4-positive cases (n = 7, 5 months) had shorter overall survival, when compared to moderate SALL4-positive (n = 46, 9 months) or SALL4-negative cases (n = 73, 7 months), respectively. Our data also suggest that SALL4 may be involved in the regulation of epithelial-mesenchymal transition (EMT) in ICC. Those results for the first time indicate an oncogenic role of SALL4 in ICC. Therefore, SALL4 may serve as a promising therapeutic target for ICC.

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is an autosomal dominant genodermatosis. It is characterized by erosions, blisters and erythematous plaques at sites of friction or intertriginous areas. The pathogenic gene of HHD has been revealed as the ATPase secretory pathway Ca2+ transporting 1 gene ( ATP2C1), which encodes the protein, secretory pathway Ca 2+/Mn 2+-ATPase 1 (SPCA1). ATP2C1 gene mutations are responsible for HHD by resulting in abnormal Ca 2+ homeostasis in the skin and giving rise to acantholysis, a characteristic pathology of HHD. In this study, a four-generation family containing three HHD sufferers was recruited. Direct sequencing of the ATP2C1 gene was performed in the proband and other available family members. Reverse-transcriptase polymerase chain reaction analysis was conducted to show the potential variant effect on ATP2C1 splicing. A novel heterozygous c.325-2A>G transition at the splice acceptor site of intron 4 in the ATP2C1 gene was identified, and it co-segregated with the disease in this family. The mutation resulted in exon 5 skipping and an in-frame deletion of 12 amino acids (p.Ala109_Gln120del) in SPCA1. This splice-site mutation may be responsible for HHD in this family. This study would further expand the mutation spectrum of the ATP2C1 gene and may be helpful in the genetic counseling and prenatal diagnosis of HHD.

The aim of the present study was to investigate the role of G‑protein coupled receptor 120 (GPR120) in esophageal cancer and explore the related mechanisms. The expression of GPR120 in esophageal cancer tissues was examined by immunohistochemistry. Correlation analysis was performed to investigate the association between the level of GPR120 and clinical parameters. The expression of GPR120 was evaluated in esophageal cancer cell lines and the effects of GPR120 on cell proliferation, clone formation, migration and invasion were evaluated in an in vitro cell model and an in vivo ectopic tumor nude mice model. In addition, the effect of GPR120 on epithelial‑mesenchymal transition (EMT), PI3K and I‑κB pathway, as well as angiogenesis and inflammation‑related cytokines was explored in order to elucidate the underlying mechanisms. Significantly increased expression of GPR120 was observed in esophageal cancer tissues compared to normal tissues. The expression of GPR120 was significantly related with histological grade, TNM stage and lymph node metastasis. GPR120 knockdown significantly decreased cell proliferation, clone formation, migration and invasion in vitro and decreased tumor growth in vivo. Furthermore significantly increased levels of E‑cadherin and decreased levels of N‑cadherin and vimentin, decreased level of Akt phosphorylation and I‑κB phosphorylation, as well as decreased levels of vascular endothelial growth factor (VEGF), interleukin‑8 (IL‑8) and cyclooxygenase‑2 (Cox‑2) and its corresponding protein PGE2 were observed as the underlying mechanisms. In conclusion, we observed an increased level of GPR120 in esophageal cancer tissues, which served as a positive regulator of the development and progression of esophageal cancer. Multiple mechanisms including EMT, PI3K and I‑κB pathway, as well as angiogenesis and inflammation‑related cytokines were involved.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer with poor responsiveness to existing drug therapies. Therefore, novel treatment strategies against ICC are required to improve survival. The aim of this study was to demonstrate the role of fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS) fusion gene in ICC. ROS was positively expressed in ICC tissues and HUCCT1 cells. Plasmids expressing ROS- and FIG-specific shRNAs were constructed and transfected into HUCCT1 cells. The results showed that single transfection of ROS- or FIG-specific shRNA inhibited HUCCT1 cell proliferation, colony formation, cell cycle progression, migration and invasion, while inducing apoptosis. Moreover, the co-inhibition of ROS- and FIG-specific shRNA exhibited stronger effects on HUCCT1 cell proliferation, apoptosis, colony formation, cell cycle progression, migration and invasion, when compared to single inhibition of ROS and FIG. Furthermore, findings of this study suggested that the AKT signaling pathway was involved in the ROS-FIG-mediated biological processes of HUCCT1 cells. In summary, the results suggest that FIG-ROS plays an oncogenic role in ICC. Additionally, ROS1-6290 and FIG-363 segments may become effective therapeutic targets for ICC harboring ROS-FIG fusion protein.