K. Tsubota

Corneal temperature in patients with dry eye evaluated by infrared radiation thermometry.

AIMS: The corneal temperature change following each blink was investigated in patients with dry eye using an infrared radiation thermometer. METHODS: Twenty patients with dry eye and 20 normal controls were enrolled in this study. Subjects kept their eyes open for 10 seconds without blinking and corneal temperature was measured every second with a recently improved infrared radiation thermometer. RESULTS: In the 20 patients with dry eye, corneal temperature change after keeping the eye open for 10 seconds was 0.21 (SD 0.06) degree C while it was 0.61 (0.28) degree C in the 20 normal patients (p = 0.0001). In an exponential equation, the inclination of the slope of a patient with dry eye was smaller than the normal. The correlation coefficient was r = 0.79 (0.16) in patients with dry eye and r = 0.90 (0.07) in normal patients. The mean K value of patients with dry eye was 0.20 (0.13)/second and that of normal subjects was 0.31 (0.19)/second (p = 0.03). CONCLUSION: Findings demonstrate the usefulness of this thermometer for measuring corneal temperature in the evaluation of dry eye. Decrease in corneal temperature with each blink in patients with dry eye was smaller than in normal subjects.

Alterations of the ocular surface epithelial MUC16 and goblet cell MUC5AC in patients with atopic keratoconjunctivitis

Background:  An increased understanding of the ocular surface at cellular level in the conjunctiva and the cornea may help explain the pathogenesis and the subsequent clinical appearance of atopic ocular allergies, which may be potentially blinding.

The differences of tear function and ocular surface findings in patients with atopic keratoconjunctivitis and vernal keratoconjunctivitis.

Background:  The pathogenesis of the ocular surface disease in atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) has not been fully understood. We tried to clarify the differences in the ocular surface status in patients with AKC, VKC, and healthy control subjects.

Transplantation of corneal endothelium with Descemet’s membrane using a hyroxyethyl methacrylate polymer as a carrier

Aims: To evaluate the histology and function of Descemet’s membrane transplanted with intact endothelium. Methods: Japanese white rabbits and human eyebank eyes were used as donors and recipients of Descemet’s membrane transplantation. Donor endothelium was hydrodissected by injecting indocyanine green from a limbal incision, and then processed as a corneal scleral button. A 6 mm diameter donor sheet was trephined, and folded in half using a 6 mm diameter polymer as a carrier. Recipient endothelium was also hydrodissected from the limbus using trypan blue to stain the Descemet’s membrane. Continuous curvilinear descemetorhexis (CCD) was performed to remove a circular section of the Descemet’s membrane using a 27 gauge cystotome. Donor tissue was inserted into the anterior chamber through a 5 mm limbal incision and apposed to the host stroma. Polymers were removed following transplantation. Similar surgical procedures were performed in both rabbits and eyebank eyes. Haematoxylin eosin stains were performed after 28 days in rabbits, and eyebank eyes were fixed immediately following surgery for endothelial cell counts. Results: Rabbit control eyes demonstrated stromal oedema caused by loss of Descemet’s membrane, whereas transplanted eyes had clear corneas. The mean (standard deviation) pachymetry of operated eyes was 376.6 (SD 32.5) μm compared with 389.6 (SD 25.1) μm in the unoperated eye. Mean endothelial density immediately following surgery in eyebank eyes was 2749 (SD 288) cells/mm2. Conclusions: Transplantation of Descemet’s membrane by CCD produces a functional graft with an optically clear interface similar to control cornea.

Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression

Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360–400 nm wavelength) suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL) elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked) and two types of contact lenses (partially VL blocked and VL transmitting). The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression.

Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion

We investigated the efficacy of lacrimal punctal occlusion surgery with a cautery device in patients with chronic GVHD (cGVHD)-related dry eye, with recanalization of puncta and recurrent punctal plug extrusion. A total of 23 puncta from 14 eyes of 10 patients with chronic GVHD (cGVHD)-related dry eye underwent punctual thermal cauterization with a high-temperature disposable cautery device. All patients were refractory to conventional treatment, including artificial tear eye drops, autologous serum eye drops and vitamin A eye drops, and had a history of recanalization and recurrent punctal plug extrusion. The effect of lacrimal punctal cauterization by thermal cautery device was evaluated by changes in subjective symptom scores, corrected distance visual acuity, Schirmers test values, fluorescein staining scores, rose bengal staining scores, and tear-film break-up time before and 3 months after the surgery. Subjective symptom scores, Schirmers test values, fluorescein and rose bengal scores, and tear-film break-up time improved significantly 3 months after the surgery. Recanalization of puncta was not observed in all the cases (0 of 14 eyes, 0%). Lacrimal punctal cauterization was effective with no recanalization and significant improvements in subjective symptoms and the ocular surface environment in cGVHD-related dry eye patients who had been refractory to conventional treatments.

A highly efficient murine model of experimental myopia

Despite the global pandemic of myopia, the precise molecular mechanism of the onset of myopia remains largely unknown. This is partially because of the lack of efficient murine myopic models that allow genetic manipulation at low cost. Here we report a highly practical and reproducible lens-induced myopia model by specially designed frames and lenses for mice. A lens power dependent myopic induction in mice was shown until minus 30 diopter lenses. The phenotype was significantly stronger than form-deprivation myopia. We presented the protocol for precise evaluations of the state of myopia, including refraction, corneal curvature and axial length using up-to-date devices. We also found that myopic mouse eyes showed decreased visual acuity on optokinetic response examination. Finally, we confirmed the anti-myopic effect of 1% atropine using this model, which showed its potential in drug screening. The strong phenotype, stable evaluation and the potential for gene manipulation utilizing the presented method in mice will accelerate the translational research of myopia.

Personalized cancer immunotherapy: Immune biomarkers and combination immunotherapy

Cancer immunotherapies utilizing tumor-specific T-cell responses, immune-checkpoint blockade, and T-cell-based adoptive cell therapy, have recently shown durable responses in advanced patients with various cancers. However, there are still cancer types and patients who do not respond to these immunotherapies. Pretreatment immune status varies in cancer patients, and it correlates with prognosis after various cancer therapies including immunotherapy. The differential T-cell response is defined by positive (e.g., number of immunogenic mutated peptides derived from mainly passenger DNA mutations in cancer cells, polymorphisms of immune-related genes of patients) and negative (e.g., oncogene activation including driver DNA mutations) immune pathways along with environmental factors (e.g., intestinal microbiota, diet, smoking, infection history). These factors could be biomarkers for selection of the patients who are likely to respond to immunotherapy and furthermore could be therapeutic targets to improve efficacy of immunotherapy possibly by combination immunotherapy with interventions on multiple key regulation points in the antitumor T-cell responses. Personalized combination immunotherapy based on the evaluation of T-cell immune status is a promising strategy for cancer treatment.

Development of Personalized Combination Cancer Immunotherapy Based on the Patients’ Immune Status

Cancer immunotherapies, particularly immune-checkpoint blockade and T cell-based adoptive cell therapy, have recently been recognized as cancer treatments that show strong and durable responses even for advanced cancer patients with multiple metastases. The major issues in the development of cancer immunotherapy are the identification of biomarkers to distinguish responders and non-responders, and the improvement of efficacy of immunotherapy possibly by combination with appropriate immune interventions targeting different key regulating points in the anti-tumor immune responses. Interestingly, pretreatment T cell immune status varies among cancer patients, and appears to correlate with responses to various cancer treatments including surgery, chemotherapy, radiation therapy, and immunotherapy. Balance of anti-tumor T cell induction pathway and immunosuppressive pathway, which are regulated by characteristics of both cancer cells and patients’ immune reactivity, may define the differential immune status among cancer patients along with environmental factors such as intestinal microbiota. The analysis of such mechanisms may lead to the identification of immune biomarkers and immune-modulating strategies for combination immunotherapies. Further research on human cancer immunopathology will lead to the development of effective personalized combination immunotherapies based on the evaluation of cancer patients’ immune status.

Cancer Induced Immunosuppression and Its Modulation by Signal Inhibitors

Although cancer immunotherapy has recently demonstrated durable responses even in patients with advanced cancer, not all patients or cancer types respond to the therapy. Pretreatment immune status varies among cancer patients and is correlated with responses to immunotherapy. Immune conditions may be defined by the balance of positive and negative pathways in the anti-tumor immune responses, which are regulated by both cancer cell characteristics and patients’ immune-reactivity along with various environmental factors. Gene alterations and signal activation define the immunological characteristics of cancer cells; tumor specific peptides derived from passenger mutations induce anti-tumor T-cells and oncogene activation (e.g. driver mutations, overexpression: MAPK, STAT3, NF-κB, β-catenin) rather promote immunosuppression. Oncogene/signal activation in cancer cells triggers multiple immunosuppressive cascades involving various immunosuppressive molecules and cells (e.g. TGF-β, IL10, IL6, VEGF, Treg, MDSC). Signal inhibitors are able to augment anti-tumor T-cell responses through multiple mechanisms including inhibition of cancer-induced immunosuppression, immunogenic cancer cell death, and enhancement of immune cell functions. Since the oncogene-signal activation status is different among patients, personalized immunotherapy combined with appropriate signal inhibitors may be considered for the development of effective immunotherapy.