Canalicular laceration repair using a novel bicanalicular silicone stent versus traditional bicanalicular stent with nasal fixation.

PURPOSE: To compare the clinical effects of two types of lacrimal stents in the repair of canalicular lacerations. METHODS: A retrospective analysis was conducted on patients with canalicular lacerations between January 2017 and December 2022. The canalicular reconstruction was performed using either the Runshi-RS bicanalicular silicone stent or the traditional bicanalicular silicone stent with nasal fixation, under a surgical microscope. The stent was placed for 3 months, and patients were followed up for more than 3 months after extubation. The anatomical and functional success rates were compared between the two groups. Anatomical success was assessed through diagnostic probing and irrigation of lacrimal passage, while functional success was determined by the patient's subjective symptoms of epiphora. RESULTS: The study included 315 patients (315 eyes) undergoing canalicular laceration repair. The Runshi-RS stent was utilized in 147 patients (46.7%), while the traditional stent with nasal fixation was employed in 168 patients (53.3%). The anatomical success rates (99.3% vs 98.8%, P = 0.642) and functional success rates (87.2% vs 88.1%, P = 0.926) were similar between the RS group and the traditional stent group. Postoperative complications were fewer (4.1% vs 10.1%, P = 0.04) and the operation time was shorter (67.1 ± 35.3 min vs 86.1 ± 43.4 min, P < 0.001) in the RS group. CONCLUSION: The Runshi-RS tube demonstrates favorable surgical outcomes for the repair of canalicular lacerations. Compared to the traditional stent with nasal fixation, the RS stent allows for shorter operation times and fewer postoperative complications in the repair of canalicular lacerations.

Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.

Processable circularly polarized luminescence material enables flexible stereoscopic 3D imaging.

Endowing three-dimensional (3D) displays with flexibility drives innovation in the next-generation wearable and smart electronic technology. Printing circularly polarized luminescence (CPL) materials on stretchable panels gives the chance to build desired flexible stereoscopic displays: CPL provides unusual optical rotation characteristics to achieve the considerable contrast ratio and wide viewing angle. However, the lack of printable, intense circularly polarized optical materials suitable for flexible processing hinders the implementation of flexible 3D devices. Here, we report a controllable and macroscopic production of printable CPL-active photonic paints using a designed confining helical co-assembly strategy, achieving a maximum luminescence dissymmetry factor (glum) value of 1.6. We print customized graphics and meter-long luminous coatings with these paints on a range of substates such as polypropylene, cotton fabric, and polyester fabric. We then demonstrate a flexible textile 3D display panel with two printed sets of pixel arrays based on the orthogonal CPL emission, which lays an efficient framework for future intelligent displays and clothing.

Morphological characterization of nevi on the caruncle conjunctiva under in vivo confocal microscopy.

Objective: This study aimed to investigate the microscopic structure and characteristics of nevi on the conjunctiva of the lacrimal caruncle by in vivo confocal microscopy. Methods: In total, four patients with nevi growing on the lacrimal caruncle conjunctiva were recruited. The morphological characteristics of the nevi were evaluated by in vivo confocal microscopy before excision surgery; the results were compared with histopathological analyses of the surgical specimens. Results: The nevi of the four patients were all located at the conjunctiva of the lacrimal caruncle, with a slightly nodular surface, mixed black and brown color, and clear boundary. The nevi were round and highly protruded on the surface of the lacrimal caruncle, with an average diameter of 4.5 ± 1.29 mm. Under in vivo confocal microscopy, the pigmented nevus cells on the conjunctiva of the lacrimal caruncle were observed to be clustered in nests with irregular boundaries. The cells were round or irregular, with clear cell boundaries, hyper-reflective at the periphery, with low reflectivity in the center. Vascular crawling was observed in some regions. Histopathological analysis showed that nevus cells were roughly equal in size and distributed in a nodular pattern. Melanin granules were observed in the cytoplasm. No atypia or mitotic figures of the cells were found. Conclusion: This study revealed that the microstructure of nevi growing on the conjunctiva of the lacrimal caruncle can be identified by in vivo confocal microscopy.

Canalicular laceration repair with a novel bicanalicular silicone tube.

PURPOSE: This study aimed to investigate the efficacy and safety of canalicular laceration repair using a novel bicanalicular silicone tube. METHODS: Retrospective and consecutive patients who underwent canalicular laceration repair using novel Runshi-RS bicanalicular silicone stents from January 2020 to February 2021 were included. The stent was placed for 3 months, and patients were followed up for more than 3 months after extubation. Demographics, causes of eyelid injuries, placement time and position of stent, and surgical outcomes at follow-up were recorded. Anatomical success was evaluated by diagnostic probing and irrigation of lacrimal passage, while functional success was evaluated by the patient's subjective symptoms of epiphora. RESULTS: This study included 43 patients with canalicular laceration. The median age was 43 years (3-75 years). The average duration of stent implantation was 12.9 weeks, and the follow-up time was 8.8 months. No complications were observed in any patients during operation and follow-up. After extubation, irrigation of the lacrimal passage in 43 eyes showed no obstruction, and the anatomical success rate was 100%. Overall, 39 patients (90.7%) had no subjective symptoms of epiphora. All patients got good cosmetic results. Furthermore, subgroup classification showed deep laceration group (distance from laceration to punctum>5 mm) accounted for 51.2%, and the functional success rate of the deep laceration group was lower than that of the shallow laceration group. CONCLUSION: Runshi-RS bicanalicular silicone stent achieved good anatomical (100%) as well as functional (90.7%) success and good cosmetic results (100%) in patients with canalicular laceration repair.

Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia.

PURPOSE: The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions. EXPERIMENTAL DESIGN: We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed. RESULTS: A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling. CONCLUSIONS: Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.

Pretarsal orbicularis oculi muscle tightening with skin flap excision in the treatment of lower eyelid involutional entropion.

BACKGROUND: To evaluate a modified technique for involutional entropion correction in a retrospective cohort study. METHODS: The patients with involutional entropion eyelid were corrected by tightening the pretarsal orbicularis oculi muscle and excising the excess skin of the lower eyelid. The patients received correction surgery from April 2013 to March 2019 were followed up for more than 6 months postoperatively. The outcome measures included the complications and the recurrence rates. RESULTS: Total 152 patients (169 eyes) were included. The mean follow-up period was 29.6 months (range: 6-36 months). Postoperative ectropion (over-correction) was observed in 1 patient with 1 eyelid (0.59%); yet, no further surgery was needed for this patient. Recurrence of entropion was found in 1 patient (0.59%). The patient with recurrent entropion received repeated surgery with the same method and achieved a good eyelid position. CONCLUSIONS: This study demonstrated that tightening the pretarsal orbicularis oculi muscle and excising the excess skin of the lower eyelid could be an effective surgical method to correct lower eyelid involutional entropion. This method is technically easy with a low recurrence rate and not associated with significant complications in Asians.

Trametinib enhances ATRA-induced differentiation in AML cells.

All-trans retinoic acid (ATRA) is only clinically useful in acute promyelocytic leukemia (APL), but not other subtypes of acute myeloid leukemia (AML). In the present study, a clinically achievable concentration of trametinib, a highly selective inhibitor of MEK, enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as AML primary cells. Moreover, trametinib-ATRA (tra-ATRA) co-treatment restored ATRA sensitivity in ATRA-resistant AML cell line, HL-60Res. The protein level of STAT3 and the phosphorylation of Akt or JNK were enhanced with tra-ATRA treatment in HL-60, U937, and HL-60Res cells, respectively. Furthermore, tra-ATRA-induced differentiation in HL-60, U937, and HL-60Res cells was inhibited by STAT3, PI3K, and JNK inhibitors, respectively. Therefore, STAT3, Akt, and JNK signaling pathways were involved in tra-ATRA-induced differentiation in HL-60, U937, and HL-60Res cells, respectively. Taken together, our findings may provide novel therapeutic strategies for AML patients.

Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells.

All-trans retinoic acid (ATRA) is considered to be the sole clinically-useful differentiating agent in the treatment of acute myeloid leukemia (AML). However, ATRA has been effective only in acute promyelocytic leukemia (APL) but not other subtypes of AML. Therefore, discovering strategies to sensitize cells to ATRA may lead to the development of ATRA-based treatments in non-APL AML patients. In the present study, a clinically-achievable concentration of enzastaurin enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as non-APL AML primary cells. Furthermore, it also restored ATRA sensitivity in ATRA-resistant cell line, HL-60Res. Mechanistically, in all these cell lines, enzastaurin-ATRA (enz-ATRA) co-treatment enhanced the protein levels of PU.1, CCAAT/enhancer-binding protein ß (C/EBPß) and C/EBPε. The activity of protein kinase C ß (PKCß) was suppressed by enz-ATRA treatment in HL-60 and HL-60Res cells. However, another PKCß-selective inhibitor mimicked the cellular and molecular effects of enzastaurin only in HL-60 cells. Furthermore, in U937 cells, enz-ATRA activated MEK and ERK, and a MEK-specific inhibitor suppressed enz-ATRA-triggered differentiation and reduced the protein levels of PU.1, C/EBPß and C/EBPε. Enz-ATRA activated Akt in HL-60 and HL-60Res cells. However, an Akt inhibitor blocked enz-ATRA-triggered differentiation and restored the protein levels of PU.1, C/EBPß and C/EBPε only in HL-60Res cells. Therefore, PKCß inhibition, MEK/ERK and Akt activation were involved in enz-ATRA-induced differentiation in HL-60, U937 and HL-60Res cells, respectively, via modulation of the protein levels of C/EBPß, C/EBPε and PU.1. Taken together, our findings may help to guide novel therapeutic strategies for AML patients.

Combination of enzastaurin and ATRA exerts dose-dependent dual effects on ATRA-resistant acute promyelocytic leukemia cells.

All-trans retinoic acid (ATRA) resistance continues to be a critical problem in acute promyelocytic leukemia (APL)-relapsed patients. In this study, a clinically achievable concentration of enzastaurin synergized with ATRA to induce differentiation and apoptosis in ATRA-resistant APL cell lines, NB4-R1 and NB4-R2. Mechanistically, although enzastaurin is a protein kinase Cß (PKCß) inhibitor, PKCß may not be required since the activity of PKCß was not suppressed by enzastaurin-ATRA (enz-ATRA) co-treatment, and another PKCß-selective inhibitor did not mimic the effects of enzastaurin. An MEK inhibitor but not a RAF-1 inhibitor suppressed enz-ATRA treatment-triggered differentiation, activation of MEK/ERK and up-regulation of CCAAT/enhancer binding protein ß (C/EBPß) and/or PU.1. Therefore, RAF-1-independent MEK/ERK signaling was required for enz-ATRA treatment-induced differentiation via modulation of the protein levels of C/EBPß and/or PU.1. Enz-ATRA treatment collapsed mitochondrial transmembrane potential without the activation of caspase-3, -6 and -7. Moreover, caspase-3/7- and caspase-6-specific inhibitors had no inhibitory effect on enz-ATRA treatment-triggered apoptosis. Therefore, enz-ATRA treatment-induced apoptosis was mitochondria-dependent but caspase-independent. Enz-ATRA treatment degraded PML-RARα, which may be involved in enz-ATRA treatment-induced dual effects and may also be beneficial for APL eradication. These findings may provide a potential therapy for ATRA-resistant APL patients.

Mantle cell lymphoma in a lacrimal gland in a female and a review of the literature.

PURPOSE: To report a rare case of Mantle cell lymphoma in lacrimal gland and review of the literature CASE REPORT: We report a case of a 59-year-old female who presented with an upper eyelid mass in the right eye for 3 months, without pain and irrigation. A computerized tomography (CT) scan showed a mass in the bilateral lacrimal gland region, more significant in right eye. The patient underwent a lacrimal gland mass excision surgery and diagnosis of mantle cell lymphoma by histopathology. Immunochemistry for CD20, CD79a, CD5, and CyclinD1 was positive. She was recommended to the Shantou cancer hospital for chemotherapy. CONCLUSION: Mantle cell lymphoma is a rare type of malignant lymphoma, over expressing CD5 and cyclin D1 antigens, which distinguishes it from other B cell lymphomas.

Effect of NF-κB inhibitor PDTC on a herpetic stromal keratitis mouse model.

PURPOSE: To investigate the effect of NF-κB inhibitor PDTC on inflammation response in mice with herpetic stromal keratitis (HSK). METHODS: A total of 120 female BALB/c mice, aged 4~6 weeks, were treated by scuffing the epithelium of the right cornea with the tip of a 30G syringe needle, and approximately 1 ×106PFU of HSV-1virus was seeded onto the corneal surface. The eye was then exposed to 170mJ/cm2 of UV light 7 weeks later, in order to induce the relapse of HSK. PDTC eye drops were adjusted to various concentrations (0.1, 1.0, and 10 mg/ml) with PBS; PBS only was used on control animals. All animals received PDTC or PBS eye drops 6 times/day, 1 drop/time, for 7 consecutive days. Mice were sacrificed at 8h, and 1, 3, and 7 d after administration. Corneal tissues were prepared for the detection of IL-1ß, IL-4, IL-6, and IL-12 by ELISA and histological study. RESULTS: Neutrophilic leukocytes and lymphocytes were found in the corneas of HSK mice. ELISA results showed fluctuating expressions of IL-1ß, IL-4, IL-6, and IL-12. The IL-1ß and IL-4 expressions were significantly lower in the high dose group than in the control group (P<0.05), while IL-6 and IL-12 expressions were significantly higher in the high dose group than in the control group (P<0.05). CONCLUSION: A high concentration of PDTC can suppress the expression of certain inflammatory factors in HSK mice while improving the expression of others.