Chemically Synthetic Membrane Receptors Establish Cells with Artificial Sense-and-Respond Signaling Pathways.

Chemically synthetic receptors that establish cells a new sense-and-respond capability to interact with outer worlds are highly desired, but rarely reported. In this work, we develop a membrane-anchored synthetic receptor (Ts-pHLIP-Pr) using DNA and peptide as the building block to equip cells with artificial signaling pathways. Upon sensing external pH stimuli, the Pr module can be translocated across the cell membrane via the conformation switch of pHLIP, enabling membrane-proximal recruitment of specific proteins to trigger downstream signaling cascades. Our experimental results demonstrate the capability of Ts-pHLIP-Pr for regulating PKCε-related signaling events upon responding to external pH reduction. With a modular feature, this receptor can be extended to elicit T cell activation through low-pH environment-induced directional movement of cytoplasmic ZAP70. Our work is expected to offer a new paradigm for intelligent synthetic biology and customized cell engineering.

POSTERIOR SCLERAL CONTRACTION TO TREAT MYOPIC FOVEOSCHISIS IN HIGHLY MYOPIC EYES.

PURPOSE: To evaluate the efficacy of posterior scleral contraction to treat myopic foveoschisis (MF). METHODS: The records of MF patients treated with posterior scleral contraction were reviewed. During posterior scleral contraction, a cross-linked fusiform strip from allogeneic sclera was used and designed axial length (AL) shortening amount was around 2.0∼3.0 mm based on preoperative AL. The middle part of the strip was placed at the posterior pole of the eye. After few aqueous humors were released, the strip was tightened to contract posterior sclera and shorten AL. Clinical data were collected at pre-operation (op) and post-op follow-ups for 12 months. RESULTS: Twenty-four eyes were collected. The AL at pre-op, post-op 1-week, 3-month, 6-month, and 12-month were 29.84 ± 1.24, 27.39 ± 1.32, 27.73 ± 1.23, 27.86 ± 1.26, and 27.91 ± 1.29 mm. There was no AL difference between post-op 6-month and 12-month (P = 0.242). The accumulated MF reattachment rate at post-op 1-week, 3-month, 6-month, and 12-month were 8.3%, 16.7%, 50.5%, and 95.8%. The best-corrected visual acuity at post-op 6-month and 12-month were 0.71 ± 0.39 (Snellen acuity 20/80) and 0.64 ± 0.37 (Snellen acuity 20/63), improving significantly compared with pre-op (P = 0.006 and <0.001). CONCLUSION: The posterior scleral contraction was effective to treat MF. The AL stabilized after post-op 6-month and MF reattached gradually with improved visual acuity up to post-op 12-month.

POSTERIOR SCLERAL CONTRACTION TO TREAT RECURRENT OR PERSISTENT MACULAR DETACHMENT AFTER PREVIOUS VITRECTOMY IN HIGHLY MYOPIC EYES.

PURPOSE: To determine the efficacy of posterior scleral contraction (PSC) to treat recurrent or persistent macular detachment after previous vitrectomy in highly myopic eyes. METHODS: We reviewed the medical records of patients with high myopia and recurrent or persistent macular detachment after previous vitrectomy treated with PSC at our hospital between April 2013 and March 2017. Fourteen eyes (14 patients; mean age, 58.93 ± 11.08 years) were included. Sclera cross-linked with genipin was used for PSC. The desired axial length decrease was 0.1-fold. The reattachment rate, best-corrected visual acuity, and axial length changes were evaluated. RESULTS: The macular reattachment rate was 100%. In seven eyes with a silicone oil tamponade, the oil was successfully removed 2 weeks to 4 months after surgery. The best-corrected visual acuity improved significantly postoperatively (Snellen acuity improved from 20/1,000-20/400) (1.75 ± 0.90 vs. 1.34 ± 0.58 logarithm of the minimal angle of resolution; P < 0.05). Eight eyes (57.14%) improved; six eyes (43.86%) remained stable. The axial length decreased significantly postoperatively (31.32 ± 3.04 vs. 29.08 ± 3.05 mm; P < 0.05). CONCLUSION: Posterior scleral contraction is safe and effective for recurrent and persistent macular detachment after previous vitrectomy in highly myopic eyes. The silicone oil is removed after PSC, and vision can be preserved in these refractory cases.

Preliminary clinical investigation of cataract surgery with a noncontact femtosecond laser system.

BACKGROUND AND OBJECTIVE: Femtosecond laser-assisted cataract surgery (FLACS) is rapidly gaining popularity due to the improved consistency and predictability for capsulorhexis. This study aimed to investigate the preliminary clinical outcomes of FLACS with a noncontact femtosecond laser system. PATIENTS AND METHODS: This prospective study enrolled 25 eyes in the trial group underwent FLACS (LLS-fs 3D, LENSAR, USA), and 29 eyes in the control group underwent conventional cataract surgery (Stellaris, Bausch & Lomb, USA). The phacoemulsification time, energy, and complications during operation were recorded. Postoperative refraction at 1 day, 1 week, 1 and 3 months, the capsulorhexis size and corneal endothelial density at 1 and 3 months were also measured. RESULTS: Compared to the control group, reduction in phacoemulsification time was 51.5% (P = 0.02), and in overall energy, 65.1% (P = 0.02) in the trial group. In the trial group and the control group, total time of cataract procedure was 10.04 ± 1.37 minutes, 10.52 ± 1.92 minutes, respectively (P = 0.31); the absolute difference between attempted and achieved capsulorhexis diameter at 1 month was 192.9 ± 212.0 µm, 626.9 ± 656.6 µm, respectively (P = 0.04), and at 3 months, 256.6 ± 181.9 µm, 572.1 ± 337.0 µm, respectively (P= 0.03); the absolute difference between attempted and achieved spherical equivalent at 3 months was 0.16 ± 0.16 D, 0.74 ± 0.65 D, respectively (P < 0.01); mean corneal endothelial cell loss at 1 month was 15.6% and 14.2%, respectively (P = 0.77), and at 3 months, 2.9%, 4.2%, respectively (P = 0.50). CONCLUSIONS: With the noncontact femtosecond laser system, FLACS can significantly improve the accuracy and repeatability of capsulorhexis, reduce the phacoemulsification time and overall energy, and enhance the predictability and stability of postoperative refraction.

Posterior scleral reinforcement on progressive high myopic young patients.

PURPOSE: To evaluate the effect of posterior scleral reinforcement in controlling high myopic axial progression in young patients. METHODS: Only one eye of each patient had posterior scleral reinforcement surgery. Before surgery and at each postoperative follow-up, the best corrected visual acuity, intraocular pressure, refractive errors, indirect ophthalmoscopy, B-type ultrasonography, and IOLMASTER reflected light biometry were performed on both eyes. The changes of axial length and the changes of refractive errors from the baseline were compared between the surgery eyes and the contralateral eyes. RESULTS: Thirty patients had a mean age of 7.5 years and a mean spherical equivalent of -9.72 diopters. The mean elongation of axial length was significantly less in the surgery eye group than that in the contralateral eye group (0.75 mm vs. 0.94 mm, p < 0.0001, paired t test) after a mean follow-up of 895 days. The surgical effect was mild but maintained during the follow-up. The eyes with staphyloma gained less surgical effect when compared with the eyes without staphyloma (p = 0.0036). There was also a notable nonstatistically significant trend for younger patients to gain a larger surgical effect (p = 0.0986). CONCLUSIONS: Posterior scleral reinforcement surgery was found effective in slowing down high myopic axial progression in young patients within the study period, but the size of the effect was small. The surgical procedure is well tolerated without vision-threatening complications.

Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism.

Terpinen-4-ol (T-4-O) is an important component of tea tree oil and has anti-inflammatory effects. Currently, there are very few studies on the mechanisms by which T-4-O improves lipopolysaccharide (LPS)-induced macrophage inflammation. In this study, LPS-stimulated mouse RAW264.7 macrophages were used as a model to analyze the effects of T-4-O on macrophage inflammatory factors and related metabolic pathways in an inflammatory environment. The results showed that T-4-O significantly decreased the expression levels of inflammatory cytokines induced by LPS. Cellular metabolism results showed that T-4-O significantly decreased the ratio of the extracellular acidification rate and oxygen consumption rate. Non-targeted metabolomics results showed that T-4-O mainly affected glutamine and glutamate metabolism and glycine, serine, and threonine metabolic pathways. qPCR results showed that T-4-O increased the transcript levels of GLS and GDH and promoted glutamine catabolism. Western blotting results showed that T-4-O inhibited the mTOR and IκB, thereby decreasing NF-κB activity. The overall results showed that T-4-O inhibited mTOR phosphorylation to promote glutamine metabolism and increased cell oxidative phosphorylation levels, thereby inhibiting the expression of LPS-induced inflammatory cytokines.

Thymol ameliorates ethanol-induced hepatotoxicity via regulating metabolism and autophagy.

Alcoholic liver disease represents a serious threat to human health. In terms of safety and acceptability, thymol is widely used in or on foodstuffs to generate odour and taste. The present study aimed to investigate the therapeutic effect and mechanism of thymol against ethanol-induced injury in liver cells. Here we found that thymol is an effective agent for reducing ethanol-induced reactive oxygen species production in mouse liver cells. Thymol improves ethanol-induced lipid accumulation, and this corresponded to altered DGAT2 mRNA expression levels. Metabolomics data analysis showed that thymol alleviated ethanol-induced changes in the levels of thirty-four metabolites including nicotinic acid and l-arginine. By utilizing pathway enrichment analysis, altered metabolites in cells treated with ethanol and ethanol plus thymol were enriched in fourteen pathways including metabolic pathways and arginine and proline metabolism. We further confirmed the alleviation of overdose nitric oxide production in cells treated with ethanol plus thymol compared with that in ethanol-treated cells. It was interesting that up-regulated LC3-II/LC3-I ratio together with higher SQSTM1 protein abundance in ethanol-treated cells were attenuated by treatment with ethanol plus thymol. Thymol ameliorated ethanol-induced reduction of HSPA8 protein abundance. In addition, chloroquine-treated cells exhibited lower HSPA8 protein abundance compared with cells simulated with ethanol plus thymol. These data reveal that improving effect of thymol on ethanol-induced metabolic alteration is related to autophagic flux restoration. Our findings indicate that thymol is an attractive option for treating ethanol-induced liver damage.

Biomechanical Considerations of Patching Material for Posterior Scleral Reinforcement Surgery.

Purpose: To characterize biomechanical properties of genipin-crosslinked human dura mater as reinforcing material for posterior scleral reinforcement (PSR) and to compare it with crosslinked human sclera. Methods: Donor dura mater and sclera were crosslinked in the same optimized genipin solution. Resistance to enzyme degradation for both materials were investigated by exposing the materials to accelerated enzyme degrading. Elastic modulus and tensile strength were measured by biomechanics testing equipment. Crosslinked human dura mater was used as reinforcing patch in PSR on 57 adult pathologic myopic eyes. The patients were followed up for an average 3 years. The main outcome was eye globe axial length change and safety profile of the reinforcing material. Results: Crosslinked dura mater demonstrated similar percentage weight loss to crosslinked sclera when exposed to enzymatic solution. Dura mater has higher density than sclera. The retaining elastic modulus after enzyme exposure was 72.02 MPa for crosslinked dura mater while 53.88 MPa for crosslinked sclera, 34% greater for crosslinked dura mater, P = 0.0186). At the end of 3 years follow-up, the mean globe axis of the surgery eyes was reduced by 1.29 mm (from 30.81 to 29.51 mm, P < 0.0001, paired t-test). Visual acuity (BCVA logMar) improved by 0.10 logMar unit which is an improvement of five letters (P = 0.0184, paired t-test). No material specific complication was noted. Conclusion: Crosslinked human dura mater may be superior to crosslinked human sclera as reinforcing material for PSR to manage progression of high myopia. This material was well tolerated on human eye.

Reduction in rectal doses of pelvic radiotherapy with excessive rectal gas extraction: a single-institution case report.

During radiotherapy for pelvic tumors, there might be insufficient radiation doses delivered that result from concerns of immediately adjacent critical organs, most notebly the rectum. Several measures have been proposed to reduce the rectal doses, such as use of a radioprotective spacer to shift the rectum away from the lesion or an endorectal balloon to reduce the internal target volume (ITV). The removal of rectal gas is supposed to achieve the similar effect by reducing the rectal volume and ITV. This is because the distance of the rectum to lesions can be increased with decreasing rectal volumes, which also makes it easy for physicists to avoid the rectum during field design. Besides, a reduced ITV can be obtained due to stability in rectal volume, as with use of an endorectal balloon. The procedure is most suitable for patients receiving stereotactic body radiotherapy (SBRT) and high dose rate brachytherapy (HDR-BR) because of limited treatment sessions. In this study, we showed that the rectal dose decreased significantly with rectal gas extraction, as manifested by dose parameters of D2 cm3 and D0.1 cm3 (the doses delivered to the most exposed 2 cm, 3 and 0.1 cm3 of the rectum, respectively). This technique is especially benefitable for candidates with excessive rectal gas fillings.

[Three-year follow-up of iris-claw phakic intraocular lens implantation for high myopia].

OBJECTIVE: To investigate long-term efficacy and safety of an iris-claw phakic intraocular lens (ICPIOL) implantation for high myopia. METHODS: A consecutive group of 86 eyes in 49 patients with -15.33±3.81 diopters (D) of myopia was implanted with the Artisan ICPIOL (Ophtec), and was evaluated preoperatively and 1, 2, 3 years postoperatively. Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), manifest refraction, intraocular pressure, and complications were evaluated. RESULTS: The implantation was successful in all of 86 eyes. Compared with preoperative data, UCVA, BCVA, and spherical equivalent (SE) were improved significantly (F=513.68, 20.88, 827.65; P<0.01). At 3-year postoperatively, UCVA in 85% eyes was 0.5 or better, in 35% was 0.8 or better; No loss of BCVA was found, 17% gained 1 line, and 59% gained 2 lines or more; SE in 81%, 54% eyes was within ±1.00 D, ±0.50 D of attempted, respectively. At 1-, 2-, 3-year follow-up, the corneal endothelial loss was 3.60%, 5.78%, 7.74%, respectively. There were 2 macular haemorrhages resulted from CNV, and 1 ICPIOL repositioning due to inappropriate iris capture. No other severe complications occurred. CONCLUSION: At 3-year follow-up, the implantation of the ICPIOL proved to be safe and effective for the correction of myopia in phakic eyes.

The efficacy of posterior scleral contraction in controlling high myopia in young people.

OBJECTIVE: To investigate the clinical effectiveness and safety of posterior scleral contraction (PSC) surgery in controlling high myopia in young people. METHODS: Twenty patients with high myopia (30 eyes) were treated with PSC. The average age for the patients was 11.45 ± 5.17 years old (range 3-22). A genipin cross-linked sclera was implanted to the posterior sclera in PSC surgery. Axial length and myopia progression rates were measured at least two years before and after PSC surgery. RESULTS: Prior to surgery, the mean AL progression was 0.73 ± 0.33 mm, compared to -0.08 ± 0.31 mm (P=0.00) post-surgery; the degree of myopia increased was -1.40 ± 0.95 D, compared to 0.18 ± 1.10 D post-surgery (P=0.00). The best corrected visual acuity (BCVA, in LogMAR) improved from 0.21 ± 0.16 preoperatively to 0.13 ± 0.13 two years after PSC (P=0.014). CONCLUSIONS: PSC can restrict AL extension and safely control high myopia progression in young people.

Posterior scleral reinforcement using genipin-cross-linked sclera for macular hole retinal detachment in highly myopic eyes.

BACKGROUND/AIMS: To investigate the surgical outcomes of posterior scleral reinforcement (PSR) using genipin-cross-linked sclera to treat macular hole retinal detachment (MHRD) in highly myopic eyes. METHODS: Nineteen patients with high myopia (19 eyes) with MHRD were treated sequentially with genipin-cross-linked PSR and were followed at least for 1 year after the surgery. The best corrected visual acuity (BCVA), axial length (AL), optical coherence tomography (OCT) outcomes and the complications were evaluated. RESULTS: Macular hole was closed in 73.7% of the eyes, foveal reattachment rate was 100%. The mean logMAR BCVA improved from 1.27±0.55 preoperatively to 0.88±0.55 postoperatively. The preoperative AL (29.88±1.97 mm) was decreased (27.73±1.84 mm) after the operation (p<0.001). CONCLUSIONS: For at least a 1-year period of follow-up, PSR with genipin-cross-linked sclera should be considered as a preferred surgical approach to treat MHRD in highly myopic eyes, especially when foveal retinoschisis is also documented.

Genipin-Crosslinked Donor Sclera for Posterior Scleral Contraction/Reinforcement to Fight Progressive Myopia.

Purpose: Myopia has become a global public health problem, particularly in East Asia where myopic retinopathy has become one of the leading causes of blindness and visual impairment in the elderly population. The purpose of this study was to evaluate the efficacy of posterior scleral contraction/reinforcement (PSCR) surgery on controlling the progressive elongation of axial length of highly myopic eyes in young patients. Methods: This is a prospective self-controlled interventional case series. Forty young patients (<18-years old) with progressive high myopia received PSCR with a genipin-crosslinked donor scleral strip for one eye and the fellow eye served as concurrent control without surgery. The main outcome measurement was the change of axial length over 2 to 3 years of follow-up. Results: Immediately after the surgery, axial length was shortened and subsequently increased by 0.32 mm over the follow-up period. In contrast, axial length of the fellow eyes increased by 0.82 mm over the same period (P < 0.001, paired t-test). PSCR delayed axial elongation in eyes with or without staphyloma. No significant change of visual acuity, cornea refractive power, or retina thickness was noted between the surgery and fellow eyes. None of the patients lost visual acuity compared with the baseline. The procedure was well tolerated with only temporary corneal refractive axis shifts that recovered by the 6-month postsurgical visit. Conclusions: PSCR with genipin-crosslinked sclera is safe and effective to restrain eye globe elongation in young patients within a 2- to 3-year follow-up period.

Comparison between toric and spherical phakic intraocular lenses combined with astigmatic keratotomy for high myopic astigmatism.

BACKGROUND: To compare the outcomes of a toric phakic intraocular lens (PIOL) and a spherical PIOL combined with astigmatic keratotomy (AK) for the correction of high myopic astigmatism. METHODS: This study enrolled patients with high myopic astigmatism, including 30 eyes (22 patients) that received a toric PIOL implantation (TICL group), and 32 eyes (24 patients) that received combined AK and a spherical PIOL implantation (AK+ ICL group). The outcomes were compared between the two groups before surgery, and at the following time points after surgery: 1 week, 1, 3, 6 months, and 1, 2 years. RESULTS: Preoperatively, the mean manifest spherical equivalent (SE) was -14.14 ± 2.12 D in the TICL group and -14.83 ± 2.79 D in the AK + ICL group (P = 0.28), and the mean manifest refractive cylinder, -2.87 ± 1.09 D and -2.58 ± 0.85 D, respectively (P = 0.28). Two years postoperatively, the mean safety index was 1.53 ± 0.55 in the TICL group and 1.60 ± 0.70 in the AK + ICL group (P = 1.00), and the mean efficacy index, 1.18 ± 0.45 and 1.38 ± 0.52, respectively (P = 0.86). The mean manifest refractive cylinder correction was 1.94 ± 1.07 D in the TICL group and 1.39 ± 0.71 D in the AK + ICL group (P = 0.02). The mean changes in SE and refractive cylinder from 1 week to 2 years were less than 0.50 D in both groups. CONCLUSIONS: Both TICL implantation and AK + ICL implantation are a good alternative for correction of astigmatism in addition to high myopia. TICL implantation has better predictability in correction of high myopic astigmatism. TRIAL REGISTRATION: NCT03202485.

Lower Beclin 1 downregulates HER2 expression to enhance tamoxifen sensitivity and predicts a favorable outcome for ER positive breast cancer.

Tamoxifen(TAM) is one of the most effective endocrine treatment for estrogen receptor(ER)-positive breast cancer, however drug resistance greatly limits benefit of it. Our purpose is to uncover the role of Beclin 1 in tamoxifen resistance and prognosis of ER positive breast cancer. We established a tamoxifen resistant ER-positive breast cancer cell subline MCF-7R presenting with higher Beclin 1 and human epidermal growth factor receptor 2(HER2) levels than MCF-7. Silencing Beclin 1 decreased levels of HER2 and significantly promoted TAM sensitivity of MCF-7 and MCF-7R in vitro. Overexpression of HER2 could reverse TAM sensitivity, which was formerly increased in Beclin 1 downregulated cell. Beclin 1 level was not only positively correlated with level of HER2 but also negatively correlated with overall survival of ER-positive breast cancer patients. Using bioinformatic methods, Beclin 1 mRNA was found to be negatively correlated with overall survival in breast cancer patients receiving TAM treatment. This study indicated for the first time that lower HER2 expression by Beclin 1 downregulation contributes to alteration of tamoxifen sensitivity and low Beclin 1 predicts favorable outcome in ER-positive breast cancer.

Myopic Macular Retinoschisis in Teenagers: Clinical Characteristics and Spectral Domain Optical Coherence Tomography Findings.

To investigate the morphological characteristics of myopic macular retinoschisis (MRS) in teenagers with high myopia, six male (9 eyes) and 3 female (4 eyes) teenagers with typical MRS identified from chart review were evaluated. All cases underwent complete ophthalmic examinations including best corrected visual acuity (BCVA), indirect ophthalmoscopy, colour fundus photography, B-type ultrasonography, axial length measurement, and spectral-domain optical coherence tomography (SD-OCT). The average age was 17.8 ± 1.5 years, average refractive error was -17.04 ± 3.04D, average BCVA was 0.43 ± 0.61, and average axial length was 30.42 ± 1.71 mm. Myopic macular degenerative changes (MDC) by colour fundus photographs revealed Ohno-Matsui Category 1 in 4 eyes, and Category 2 in 9 eyes. Posterior staphyloma was found in 9 eyes. SD-OCT showed outer MRS in all 13 eyes, internal limiting membrane detachment in 7 eyes, vascular microfolds in 2 eyes, and inner MRS in 1 eye. No premacular structures such as macular epiretinal membrane or partially detached posterior hyaloids were found. Our results showed that MRS rarely occurred in highly myopic teenagers, and was not accompanied by premacular structures, severe MDC, or even obvious posterior staphyloma. This finding indicates that posterior scleral expansion is probably the main cause of MRS.

The efficacy and safety of posterior scleral reinforcement using genipin cross-linked sclera for macular detachment and retinoschisis in highly myopic eyes.

BACKGROUND/AIMS: To evaluate the efficacy and safety of posterior scleral reinforcement (PSR) using genipin cross-linked sclera as the material to treat macular detachment and retinoschisis, both without macular hole, in highly myopic eyes. METHODS: Twenty-one patients with highly myopic eyes (24 eyes) with macular detachment and retinoschisis were treated sequentially with genipin cross-linked PSR and were followed for at least 1 year after surgery. The best-corrected visual acuity (BCVA), spherical equivalent (SE) power, axial length (AL), optical coherence tomography, and the complications were evaluated. RESULTS: The mean SE decreased from -13.81±4.67 D preoperatively to -9.64±4.86 D postoperatively, while the improvement in the logMAR BCVA values was from 1.24±0.57 before surgery to 1.03±0.57 after surgery. The preoperative AL (29.73±2.31 mm) was decreased (28.08±2.08 mm) after the operation. The retina in 21 eyes (87.5%) was successful reattached and the macular detachment was significantly decreased in two eyes; a macular hole occurred in one eye. CONCLUSIONS: For at least a 1 year period of follow-up, PSR with genipin cross-linked sclera was safe and effective to treat macular detachment and retinoschisis in high myopia when a macular hole was not present. The reinforcement effect tended to be stabilised and maintained for 6 months after treatment.