IKZF4/NONO-RAB11FIP3 axis promotes immune evasion in gastric cancer via facilitating PD-L1 endosome recycling.

As an immune checkpoint protein expressed by diverse cancer cells, programmed death ligand 1 (PD-L1) facilitates immune evasion by interacting with programmed cell death-1 (PD-1) on T cells. Despite the clinical benefits observed in various cancer types, strategies targeting PD-1/PD-L1 have demonstrated limited efficacy in gastric cancer (GC). Furthermore, the regulation of PD-L1, especially at post-translational modification levels, remains largely unknown. Therefore, it is crucial to elucidate the mechanisms governing PD-L1 expression to enhance anti-tumor immunity. In this study, we have identified that IKAROS family zinc finger 4 (IKZF4) and Non-POU domain-containing octamer-binding (NONO) synergistically regulate and enhance the expression of RAB11 family-interacting protein 3 (RAB11FIP3) in GC. The IKZF4/NONO-RAB11FIP3 axis facilitates the endosomal recycling of PD-L1, particularly on the cell membrane of GC cells. Moreover, overexpression of RAB11FIP3 mitigates the hypo-expression of PD-L1 protein resulting from IKZF4 or NONO deletion. Functionally, the silencing of RAB11FIP3 or IKZF4 promotes T cell proliferation, and enhances T-cell cytotoxicity towards GC cells in vitro, which further inhibits tumor immune evasion in mice via increasing the infiltration of CD8+ T cells into the tumor microenvironment (TME) to suppress GC progression. Our study suggests that the IKZF4/NONO-RAB11FIP3 axis promotes immune evasion by facilitating PD-L1 endosome recycling, thus presenting a potential therapeutic target for GC treatment.

Joint optic disc and cup segmentation based on elliptical-like morphological feature and spatial geometry constraint.

Glaucoma is a chronic degenerative disease that is the second leading cause of irreversible blindness worldwide. For a precise and automatic screening of glaucoma, detecting the optic disc and cup precisely is significant. In this paper, combining the elliptical-like morphological features of the disc and cup, we reformulate the segmentation task from a perspective of ellipse detection to explicitly segment and directly get the glaucoma screening indicator. We detect the minimum bounding boxes of ellipses firstly, and then learn the ellipse parameters of these regions to achieve optic disc and cup segmentation. Considering the spatial geometry prior knowledge that the cup should be within the disc region, Paired-Box RPN is introduced to simultaneously detect the disc and cup coupled. In addition, boundary attention module is introduced to use edges of the disc and cup as an important guide for context aggregation to improve the accuracy. Comprehensive experiments clearly show that our method outperforms the state-of-the-art methods for optic disc and cup segmentation. Simultaneously, the proposed method also obtains the good glaucoma screening performance with calculated vCDR value. Joint optic disc and cup segmentation, which utilizes the elliptical-like morphological features and spatial geometry constraint, could improve the performance of optic disc and cup segmentation.

Differences in Neuropathic Pain and Radiological Features Between AQP4-ON, MOG-ON, and IDON.

Purpose: The purpose of this study was to investigate pain and radiological features of different types of first-episode demyelinating optic neuritis (ON). Methods: Eighty-three patients presenting with first-episode aquaporin-4 (AQP4) antibody-associated ON (AQP4-ON; n = 28), myelin oligodendrocyte glycoprotein (MOG) antibody-associated ON (MOG-ON; n = 26) and idiopathic demyelinating optic neuritis (IDON, n = 29) were included in this retrospective case-control study. We assessed optic nerve lesions on magnetic resonance imaging (MRI), acute pain associated with onset of optic neuritis and clinical characteristics of those ON patients with different serum autoantibody status. Results: 24 AQP4-ON patients (85.75%), 23 MOG-ON patients (88.5%) and 24 IDON patients (82.8%) suffered from ON-associated pain. MOG-ON had mostly retro-orbital pain; AQP4-ON and IDON had mostly neuropathic pain. In addition, pain was more severe in AQP4ON patients than in other ON patients. In MRI, bilateral involvement was more common in AQP4-ON than IDON (26.9 and 3.7%); radiological optic nerve head swelling was more common in MOG-ON than in AQP4-ON and IDON (68.0 vs. 23.1 vs. 25.9%). MRI lesion in peri-optic nerve sheath was more common in AQP4-ON (53.8 vs. 16.0 vs. 3.7%). In 70 patients with ON-associated pain, gadolinium enhancement of orbital optic nerve was most common in MOG-ON patients (82.4 vs. 55.0 vs. 33.3%, P = 0.018), and enhancement of optic chiasma was most common in AQP4-ON patients (40.0 vs. 5.9 vs. 6.7%, P = 0.015). Perineural and orbital enhancement was observed only in patients with MOG-ON (P < 0.001). The length of enhancement was longer in AQP4-ON patients than in MOG-ON and IDON patients. Conclusion: Pain is a common symptom in patients with all types of demyelinating ON. AQP4-ON is frequently associated with severe ON-associated pain and longitudinally extensive optic nerve inflammatory lesions. Intra-orbital and peri-optic inflammation were more frequently observed in patients with MOG-ON, which was closely related to optic disc swelling and retro-orbital pain provoked by eye movements.

Down-Regulated CLDN10 Predicts Favorable Prognosis and Correlates With Immune Infiltration in Gastric Cancer.

Background: CLDN10, an important component of the tight junctions of epithelial cells, plays a crucial role in a variety of tumors. The effect of CLDN10 expression in gastric cancer, however, has yet to be elucidated. Methods: Differential expression of CLDN10 at the mRNA and protein levels was evaluated using Oncomine, ULCAN, HPA and TIMER2.0 databases. Real-time polymerase chain reaction (RT-PCR) was utilized to further verify the expression of CLDN10 in vitro. Correlations between CLDN10 expression and clinical outcomes of gastric cancer were explored by Kaplan-Meier Plotter. Gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) were performed via LinkedOmics and GeneMANIA. The correlations between CLDN10 expression and immune cell infiltration and somatic copy number alternations (SCNA) in gastric cancer were explored by TIMER2.0 and GEPIA2.0. Results: CLDN10 expression was lower in gastric cancer compared to adjacent normal tissues, and associated with better prognosis. CLDN10 also showed significant differences at different T stages, Lauren classification, treatments and HER2 status. PPI and GSEA analysis showed that CLDN10 might be involved in signal transmission, transmembrane transport and metabolism. In some major immune cells, low expression of CLDN10 was associated with increased levels of immune cell infiltration. In addition, it was found that different SCNA status in CLDN10 might affect the level of immune cell infiltration. Furthermore, the expression of CLDN10 was significantly associated with the expression of several immune cell markers, especially B cell markers, follicular helper T cell (Tfh) markers and T cell exhaustion markers. Conclusion: Down-regulated CLDN10 was associated with better overall survival (OS) in gastric cancer. And CLDN10 may serve as a potential prognostic biomarker and correlate to immune infiltration levels in gastric cancer.

A Novel sRNA in Shigella flexneri That Regulates Tolerance and Virulence Under Hyperosmotic Pressure.

Regulation of the environmental stress response and virulence of Shigella flexneri may involve multiple signaling pathways; however, these mechanisms are not well-defined. In bacteria, small regulatory RNAs (sRNAs) regulate bacterial growth, metabolism, virulence, and environmental stress response. Therefore, identifying novel functional sRNAs in S. flexneri could help elucidate pathogenic adaptations to host micro-environmental stresses and associated virulence. The aim of this study was to confirm the presence of an sRNA, Ssr54, in S. flexneri and to determine its functions and possible mechanism of action. Ssr54 was found to regulate tolerance and virulence under hyperosmotic pressure. Its expression was verified by qRT-PCR and Northern blotting, and its genomic position was confirmed by 5'-rapid amplification of cDNA ends. Ssr54 expression was significantly decreased (~ 80%) under hyperosmotic conditions (680 mM NaCl), and the survival rate of the Ssr54 deletion strain increased by 20% under these conditions. This suggested that Ssr54 has been selected to promote host survival under hyperosmotic conditions. Additionally, virulence assessment, including guinea pig Sereny test and competitive invasion assays in mouse lungs, revealed that Ssr54 deletion significantly decreased S. flexneri virulence. Two-dimensional gel analyses suggest that Ssr54 may modulate the expression of tolC, ompA, and treF genes, which may affect the virulence and survival of S. flexneri under osmotic pressures. Furthermore, treF expression has been shown to improve the survival of S. flexneri under osmotic pressures. These results suggest that Ssr54 has a broad range of action in S. flexneri response to hyperosmotic environmental stresses and in controlling its virulence to adapt to environmental stresses encountered during host infection.

[Usefulness of self-made gasbag double-cannula stool drainage device for prevention of anastomotic leakage following anterior resection].

OBJECTIVE: To evaluate the efficacy of self-made gasbag double-cannula stool drainage device for prevention of anastomotic leakage following anterior resection. METHODS: Clinical data of 169 rectal cancer patients in the 8th Affiliated Hospital of Sun Yat-sen University between October 2010 and October 2016 were retrospectively analyzed. Among them, a self-made gasbag double-cannula stool drainage device was placed in 71 patients(stool drainage group), and the remaining 98 patients were taken as control. After an anastomosis, the drainage device was transanally placed by the assistant and the distal tube of drainage device was stretched more than 15 cm from anastomosis. The gasbag was inflated to fully expand the intestine. The main tube was fixed on perianal skin with 7-0 suture, kept more than 3-5 cm outside the anus, and connected to the drainage bag. The incidence of anastomotic leakage was compared between the two groups. RESULTS: The baseline data were similar between the two groups (all P>0.05). The differences in operative time, intraoperative blood loss, and time to bowel function recovery were not statistically significant (all P>0.05), however, time to oral intake and postoperative stay were shorter in stool drainage group as compared to the control group (both P<0.05). There was no perioperative death in both groups. In stool drainage group, there were 6 cases whose drainage device was pulled out within 48 hours due to intolerance. The ruptured gasbag was replaced 5 times and the tube was clogged by fecal material 21 times. After flushing, the tube did not recanalized and was pulled out in 3 cases. The incidence of anastomotic leakage in stool drainage group was significantly lower than that in the control group (2.8% vs. 11.2%, P=0.043). As for the low anastomosis (the distance to anal verge less than 5 cm), the incidence of anastomotic leakage in stool drainage group was also significantly lower than that in the control group (2.3% vs. 15.4%, P=0.028), while as for the high anastomosis, the difference was not statistically significant (3.6% vs. 3.0%, P=0.906). Logistic regression analysis revealed that the presence of a stool drainage device was an independent protective factor for anastomotic leakage (OR=0.316, 95%CI:0.114 ~ 0.769, P=0.003). CONCLUSIONS: The self-made gasbag double-cannula stool drainage device effectively prevents anastomotic leakage after anterior resection of rectal cancer. However it is not suitable for those patients with high anastomosis.

A new classification for epidemiological study of mechanical eye injuries.

OBJECTIVE: Considering the difficulty in classifying some cases with eye trauma by Birmingham Eye Trauma Terminology (BETT) in our epidemiological study, we introduce a new classification for epidemiological study of mechanical eye injuries based on BETT. METHODS: A retrospective investigation was carried out in 31 hospitals from January 2005 to December 2010. All medical records of inpatients with eye injuries were reviewed. A total of 10 718 patients (11 227 eyes) were diagnosed as mechanical eye injuries. All mechanical eye injuries were tried to be classified using BETT. While some eye injuries were difficult to categorize. We recorded the injury type and case number. A new classification based on BETT was also used for the same project. RESULTS: Of 10 718 patients (11 227 eyes) with mechanical eye injuries, the following cases cannot be classified by BETT: 1 488 patients (1 559 eyes) with merely orbital or ocular adnexa injury, 1 961 (2 054) globe injuries associated with orbital or ocular adnexa injury, 271 (284) ocular surface foreign body (OSFB) or ocular wall foreign body (OWFB), 77 (89) contusion, 9 (11) lamellar laceration associated with OSFB or OWFB, 29 (30) rupture associated with OSFB, OWFB or intraocular foreign body and 60 (62) lace- ration associated with OSFB or OWFB. While according to our new classification, all eye injuries can be categorized without any difficulty. CONCLUSION: Difficulty in classifying some eye injuries in epidemiological study by BETT brings some trouble to our study, which can be solved by our new eye injury classification to some extent. It is hoped that other ophthalmologists present better ones to make the classification more perfect.

Characterization of retinal nerve fiber layer thickness changes associated with Leber's hereditary optic neuropathy by optical coherence tomography.

In the present study, the changes in the retinal nerve fiber layer (RNFL) thickness associated with Leber's hereditary optic neuropathy (LHON) were examined by Cirrus high definition-optical coherence tomography (OCT), and the correlation between the RNFL thickness and the best corrected visual acuity (BCVA) was evaluated. A cross-sectional study was performed. Sixty-eight eyes from patients with LHON and 30 eyes from healthy individuals were scanned. Affected eyes were divided into 5 groups according to disease duration: Group 1, ≤3 months; group 2, 4-6 months; group 3, 7-9 months; group 4, 10-12 months; and group 5, >12 months. The RNFL thickness of the temporal, superior, nasal and inferior quadrants and the 360° average were compared between the LHON groups and the control group. The eyes in groups 1 and 2 were observed to have a thicker RNFL in the superior, nasal and inferior quadrants and a higher 360°-average RNFL thickness compared with those of the control group (P<0.05), the RNFL was observed to be thinner in the temporal quadrant in groups 1 and 2. The eyes in groups 3 and 4 showed a thinner RNFL in the temporal (P=0.001), superior and inferior (both P<0.05) quadrants, and a lower 360°-average RNFL thickness as compared with controls (P=0.001). No significant correlation was identified between BCVA and RNFL thickness. RNFL thickness was observed to undergo a unique process from thickening to thinning in the patients with LHON. Changes in different quadrants occurred at different time periods and the BCVA was not found to be correlated with RNFL thickness.

Ocular manifestations of intracranial germinomas: three cases report and literature review.

Intracranial germinomas are malignant neoplasms of gonadal origin, which have some features in terms of age, sex, and clinical manifestations. They mainly occur in children and adolescents. Patients with intracranial germinomas mainly manifest with hypothalamic pituitary axis dysfunction and/or compression syndromes. Visual disturbance is one of the most significant clinical presentations, which is mainly caused by tumor cell infiltration into the optic pathway. In this article, we present three cases of patient with intracranial germinoma to analyze the ocular manifestations. All the three patients presented with endocrine symptoms in the early stage and with visual disturbances (including decreased visual acuity and visual field defects) later. In general, germinoma is diagnosed by its characteristic radiological appearance, supported by tumor markers and/or stereotactic biopsy. However, decisive diagnoses were established when ocular manifestations were presented. A suspicion for germinoma should be considered, when young patients manifest visual disturbances accompanied by endocrine symptoms.

Clinical analysis of the etiology of optic neuritis in patients at different ages in china.

PURPOSE: To determine the etiology of optic neuritis in patients of different ages in China. METHODS: Records of optic neuritis patients who were hospitalized in the Department of Neuro-ophthalmology, General PLA Hospital, Beijing, between January 1, 2011 and December 31, 2011 were retrospectively reviewed. RESULTS: A total of 132 patients were divided into three groups by age. The percentage of patients aged ≤ 16 years, 16-45 years and >45 years were 17.4% (23/132), 54.6% (72/132), and 28.0% (37/132) respectively. The distribution of etiologies differed significantly among the three groups (X2=23.2, P=0.026). The percentage of idiopathic demyelinating optic neuritis was the highest in the 16-45 group (44.4%), and the proportion of neuromyelitis optical was the highest in the ≤ 16 years group. Infectious optic neuritis was more frequently seen in patients aged ≤ 16 years and >45 years. The source of infection was viral (n=2), nasosinusitis (n=1) and bacterial (n=1) in the ≤ 16 years group and neurosyphilis (n=3) and nasosinusitis (n=1) in the >45 years group. The percentage of paraneoplastic syndrome in the >45 years group was 8.11% (3/37). CONCLUSION: The etiology of optic neuritis in patients at various ages differed significantly.

Laser in situ keratomileusis surgery is not safe for military personnel.

OBJECTIVE: To investigate the relationship between eye injury and laser in-situ keratomileusis (LASIK) surgery in military personnel. METHODS: This retrospective study collected the data from 27 evacuation hospitals of Chinese army. All medical records of eye injuries in military personnel admitted to the 27 hospitals between January 2006 and December 2010 were reviewed. Patients'detailed information was analyzed, including the injury time, place, type, cause, as well as examination, treatment and outcome. RESULTS: There were 72 eye-injured patients who had been treated by LASIK before. The incidence was rising year by year. Among them, 69 patients were diagnosed with mechanical ocular injury and 3 with non-mechanical ocular injury; 29 patients had traumatic flap-related complications and 21 patients need surgery. There was statistical difference when compared with those having no refractive surgery history. Visual acuity recovered well at discharge. CONCLUSION: There is a high risk of potential traumatic flap problems after LASIK and it is not recommended in army service.

Epidemiology of eye injuries sustained by military personnel in China.

OBJECTIVE: To investigate the epidemiological characteristics of eye injuries sustained by military personnel in Chinese army. METHODS: Eleven military evacuation hospitals located in different regions were selected for this study. We reviewed all the medical records of eye injuries sustained by military personnel between January 2005 and December 2009. Patients'information was collected. All data were put into database and analyzed statistically. RESULTS: Totally there were 415 inpatients with eye injuries (442 eyes) and their mean age was 24.40 years. Eye injury accounts for 13.51% of all eye diseases in this study. From 2006 to 2009, the number of eye injury increased gradually. Among them, 175 (42.17%) were injured in leisure time, and 145 (34.94%) in working time. Twenty-two (5.30%) patients had an eye surgery or history of eye disease before injury. In all, 246 patients (59.28%) were sent to evacuation hospital within 24 hours and 64 (56.64%) underwent surgeries in 24 hours after injury. There were 389 patients (93.73%) hospitalized for 1 time. Visual acuities of 187 eyes (42.31%) were grade 1 (larger than or equal to 20/40) after injury. When discharge, 349 eyes (78.96%) obtained a visual acuity of grade 1. CONCLUSION: Eye injury has a very frequent incidence in Chinese army and much more attention should be paid to prevent it.

The survey of the causes of eye injury of various services in China.

The cause of eye injury in various services may be different. Preventing the injury according to the cause would be more effective. We investigated 502 (549 eyes) cases of ocular injury in 21 military hospitals in China. Sports-related injury was the first cause of ocular injury (181/502, 36.1%), and it was more often seen in navy and air force personnel. A total of 69.1% of sports-related ocular injuries were caused by playing basketball and 18.8% by playing football. Work-related injury was the second cause (140/502). The highest ratio of work-related injury was in the surface warship force (31/67, 46.3%). The ratios of military training-related injury in the army and armed police were 21.4% and 21.3%, respectively, but it is only 4.4% in the navy. The analysis of training subjects showed that about 49.2% of injuries occured during skill training, such as parachuting and operating firearms, and 29.5% occurred during physical exercise or counter-acting exercises. We also found that the ratio of sports-related injury increased and military training-related injury decreased with the level of education.

[Analysis on characteristics of ocular trauma caused by military affairs in soldiers].

OBJECTIVE: To investigate and analyze the epidemiological, clinical and prognostic characteristics of ocular trauma in soldiers caused by military affairs and compared with those in trauma caused by non-military causes. METHODS: A retrospective study on eye injury cases of military inpatients in 15 military general hospitals from 2001 to 2005 was performed and the data of 716 cases (772 eyes) were statistically analyzed. RESULTS: Three hundred and sixty inpatients (398 eyes) caused by military affairs accounted for 50.28% (360/716) of all military inpatients with eye injuries. The difference between trauma cases caused by military affairs and non-military affairs included: higher male/female ratio, 99.45% (358/360), 96.38% (343/356) (χ(2) = 6.92, P = 0.009) and younger age, averaged (23.14 ± 5.23) yrs vs. (26.94 ± 10.45) yrs (t = -6.163, P < 0.001). The most frequent causes in trauma caused by military affairs were explosion (12.78%, 46/360) and construction of national defense (12.78%, 46/360); whereas sports in leisure accounted for 35.96% cases in trauma caused by non-military affairs. The other characters of trauma caused by military affairs included: more non-mechanical globe injuries, 12.06% (48/398), 2.67% (10/374) (χ(2) = 23.12, P < 0.001), less mechanical injuries, 81.91% (326/398), 90.64% (339/374) (χ(2) = 11.59, P = 0.001); a higher proportion of open globe injuries (especially intraocular foreign body); more full-thickness laceration of globe wall needed primary repair, 57.26% (71/124), 84.78% (39/46) (χ(2) = 11.13, P = 0.001); higher rates of enucleation/evisceration, 4.52% (18/398), 1.07% (4/374), (χ(2) = 7.10, P = 0.008), lower vision, 15.33% (61/398), 4.81% (18/374) (χ(2) = 22.07, P < 0.001) and more blindness, 25.38% (101/398), 10.42% (39/374) (χ(2) = 28.03, P < 0.001); less eyes with final vision ≥ 0.5, 28.02% (111/396), 35.66% (133/373) (χ(2) = 4.81, P = 0.028) and less eyes with increasing vision, 68.68% (272/398), 76.41% (285/374) (χ(2) = 5.35, P = 0.021). CONCLUSIONS: Eye injury caused by military affairs is more severe and poorer in prognosis and is the direct factor that causing the decrease of military power. Emphasis should be placed on the prevention and treatment of eye injuries caused by military affairs.

[Epidemiological characteristics of eye injury among soldiers in 15 military hospitals].

OBJECTIVE: To investigate and analyze the epidemiological characteristics of eye injury among military inpatients. METHODS: Data of eye injury among military inpatients from 15 military general hospitals during 2001 - 2005 were recorded and statistically analyzed. RESULTS: There were 716 military inpatients with eye injuries, taking up 7.41% of the whole ocular trauma inpatients in corresponding time period. Military inpatients with eye injuries were admitted more in spring and summer; with sex ratio as 46.73:1; mean age as (24.99 +/- 8.40) years and 82.27% in 17-29 years while 7.82% were binocular injuries. A certain proportion of the complication appeared after the myoporthosis operations. Mechanical and non-mechanical eye injuries took up 92.49% and 7.51% respectively. Sports (17.62%), explosion (11.92%) and fighting (11.40%) related factors were the main causes of injuries. 51.55% of the accidents took place during working or training processes and 30.31% was on military training sites. At discharge, 22 eyeballs were removed mainly due to open globe injuries, 9 eyes with no light perception but vision acuity equalled to or more than 0.5 in 62.16% of the patients. CONCLUSION: Of those eye injury inpatients, military training and construction for defense were the main causes related to occupational eye injuries among soldiers. Mutilation power of eye injury should not be ignored and epidemiological survey on military eye injuries need to be carried out more extensively.