Lacrimal Gland Research Articles

Electroacupuncture modulates the TLR4-NF-κB inflammatory signaling pathway to attenuate ocular surface inflammation in dry eyes of type 2 diabetic rats.

Bioinformatics analysis was performed to reveal the underlying pathogenesis of type 2 diabetes (T2DM) dry eye(DE) and to predict the core targets and potential pathways for electroacupuncture (EA) treatment of T2DM DE, in which key targets such as Toll-likereceptor4 (TLR4), NF-κB and Tumor necrosis factor-α (TNF-α) may be involved. Next, streptozotocin and a high-fat diet were used to generate T2DM-DE rats. Randomly picked EA, fluorometholone, model, and sham EA groups were created from successfully modelled T2DM DE rats. Six more rats were chosen as the blank group from among the normal rats. The results of DE index showed that EA improved the ocular surface symptoms.HE staining showed that EA attenuated the pathological changes in the cornea, conjunctiva and lacrimal gland of T2DM DE rats. EA decreased the expression of TLR4, MyD88, P-NF-κB P65, and TNF-α in the cornea, conjunctiva, and lacrimal gland, in accordance with immunofluorescence and Western blot data. Thus, EA reduced ocular surface symptoms and improved pathological changes of cornea, conjunctiva, and lacrimal gland induced by T2DM DE inT2DM DE rats, and the mechanism may be related to the inhibition of overactivation of the TLR4/NF-κB signaling pathway by EA and thus attenuating ocular surface inflammation.

Mucosa-associated lymphoid tissue lymphoma of the lacrimal gland: A case report and literature review.

The most common subtype of primary lymphoma of the ocular adnexa is the mucosa-associated lymphoid tissue (MALT) subtype. MALT lymphoma of the lacrimal gland is relatively rare among the lacrimal gland tumors, and the early clinical symptoms are atypical, which can easily lead to misdiagnosis and missed diagnosis. Here, we report a case of MALT lymphoma of the lacrimal gland and explore its clinical manifestations, pathological characteristics, management, and pathogenesis, with the aim of helping clinicians gain an in-depth understanding of ocular adnexal MALT lymphoma. A 60-year-old man presented to our hospital with proptosis and diplopia. The right eye deviated and shifted toward the lower part of the nose. Orbital enhanced magnetic resonance imaging suggested a mass with a maximum cross-section of 3.2 × 2.1 cm. T1 weighted image was isointense, and the enhancement was more uniform and obvious. The right orbital mass was treated surgically, and the final pathology report was MALT lymphoma. After the pathological report was released, the patient was transferred to the hematology department for further diagnosis and no further treatment was given eventually. Seven months later, the patient did not complain of discomfort. Whole-body positron emission tomography-computed tomography, superficial lymph node examination and orbital magnetic resonance imaging revealed no abnormal changes. The clinical manifestations of MALT lymphoma are heterogeneous. Imaging examination is important for assessing the size of the tumor and its relationship with adjacent tissues. Postoperative pathological examination may provide further evidence for the evaluation of the patient's surgical efficacy and prognosis. Management of MALT lymphoma of the lacrimal gland requires a multidisciplinary approach involving ophthalmologists, hematologists, and radiotherapists.

#1494 Immunotactoid glomerulopathy: a comprehensive analysis of three cases

Abstract Background Immunotactoid glomerulopathy (ITG) is an uncommon cause of glomerular disease encountered in approximately 0.06% of native kidney biopsies. This fibrillary disease is strongly associated with haematologic disorders, including lymphoma (mainly chronic lymphocytic leukaemia/small lymphocytic lymphoma), monoclonal gammopathy, and multiple myeloma. It is usually managed with oral steroids and/or treatment of an underlying lymphoproliferative disorder. Here, we report three cases of ITG, all female patients with varying severity of the disease, timing of malignancy and required treatment. Case Scenarios: Case 1: A 76-year-old lady with no significant medical background presented in May 2020 with confusion and progressive peripheral oedema. She had AKI (serum creatinine 210 µmol/L from baseline 68 µmol/L) and a sodium of 104 mmol/l. Urine PCR was 1182 mg/mmol. She was admitted to the ITU, where hyponatraemia was managed with a good clinical response. Blood screening showed negative immune, myeloma and virology screens. Complement was low. A renal biopsy showed a diagnosis of ITG. She had an extensive malignancy screen, but no malignancy was detected. She was started on prednisolone 60 mg once daily and eventually weaned off the drug by March 2021, as she maintained remission of her disease. Two years after her initial presentation, she was seen by the ophthalmologist for a right lacrimal gland mass. This was excised, and a biopsy revealed a MALT Lymphoma. Case 2: A 50-year-old lady with splenomegaly being investigated under the haematology service was referred to our renal clinic for proteinuria in June 2019. Her serum creatinine was within normal limits, and her UPCR was 302 mg/mmol. She had no paraprotein in her blood, low serum immunoglobulins, low C3 and a negative viral screen. Perindopril, initiated by her GP, was up-titrated. Renal biopsy revealed features in keeping with Immunotactoid Glomerulopathy, and completed haematological investigations revealed Chronic Lymphocytic Leukaemia. Her UPCR peaked at 842 mg/mmol before reducing to 190 mg/mmol within a year after treatment with Veneclotax and Rituximab after not tolerating FCR (Fludarabine, Cyclophosphamide, Rituximab) Chemotherapy. Case 3: A 69-year-old lady presented to the renal clinic with proteinuria in September 2018. She had a background of breast cancer diagnosed in 2007 (She had surgical resection followed by radiotherapy). Her 24-hour urine protein was 2g, and UPCR was 155 mg/mmol. Serum creatinine was 81 µmol/l and eGFR 66 ml/min. P- ANCA was positive, while PR3 and ANA were negative. She had bilateral leg oedema due to long-standing lymphedema. The biopsy report showed immunotactoid glomerulopathy. Regular surveillance of previous breast cancer with mammography and CT-CAP has shown no evidence of malignancy recurrence, hepatitis virology and paraprotein were negative, and C3/C4 were within normal limits. She had improved UPCR and maintained normal kidney function on full-dose Losartan. Conclusion Immunotactoid Glomerulopathy is a rare form of glomerular disease with a strong association with lymphoproliferative malignancies, which may precede, occur concomitantly or present years after the initial diagnosis. This common association highlights the need for diligence in screening for malignancy in each case, and it is a reason for careful follow-up of these patients. Treatment of underlying disorders is associated with positive renal outcomes, and in some cases, there is a good response to steroids.

IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.

AS101 regulates the Teff/Treg balance to alleviate rabbit autoimmune dacryoadenitis through modulating NFATc2

Sjögren's syndrome (SS) dry eye can cause ocular surface inflammation and lacrimal gland (LG) damage, leading to discomfort and potential vision problems. The existing treatment options for SS dry eye are currently constrained. We investigated the possible therapeutic effect and the underlying mechanism of AS101 in autoimmune dry eye. AS101 was injected subconjunctivally into a rabbit model of autoimmune dacryoadenitis and its therapeutic effects were determined by evaluating clinical and histological scores. The expressions of effector T cells (Teff)/regulatory T cells (Treg)-related transcription factors and cytokines, inflammation mediators, and transcription factor NFATc2 were measured by quantitative real-time PCR and/or Western blot both in vivo and in vitro. Additionally, the role of NFATc2 in the immunomodulatory effects of AS101 on T cells was explored by co-culturing activated peripheral blood lymphocytes (PBLs) transfected with NFATc2 overexpression lentiviral plasmid with AS101. AS101 treatment potently ameliorated the clinical severity and reduced the inflammation of LG. Further investigation revealed that AS101 treatment led to decreased expression of Th1-related genes (T-bet and IFN-γ) and Th17-related genes (RORC, IL-17A, IL-17F, and GM-CSF) and increased expression of Treg-related gene Foxp3 in vivo and in vitro. Meanwhile, AS101 suppressed the expression of TNF-α, IL-1β, IL-23, IL-6, MMP-2, and MMP-9. Mechanistically, AS101 downregulated the expression of NFATc2 in inflamed LGs. Overexpression of NFATc2 in activated PBLs partially blunted the effect of AS101 on Teff suppression and Treg promotion. In conclusion, AS101 is a potential regulator of Teff/Treg cell balance and could be an effective treatment agent for SS dry eye.

The Role of Aquaporin 4 in Lacrimal Gland Ductal Fluid Secretion in Mice.

Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4 mRNA levels have been observed in experimental dry eye and during pregnancy, the impact of AQP4 in LG ductal fluid production remains unclear. In our recent work, the role of AQP4 in LG ductal fluid secretion was investigated utilizing wild type (WT) and AQP4 knock out (KO) mice. Tear production was assessed in both WT and KO animals. Immunostaining was used to identify AQP4 protein. Duct segments were harvested from LGs of WT and KO mice. Fluid secretion and filtration permeability (Pf) were quantified using video-microscopy. Ductal tear production, elicited by a cell-permeable cAMP analogue (8-bromo cAMP), carbachol, vasoactive intestinal peptide (VIP), and phenylephrine (PHE), were assessed in both WT and KO ducts. A higher expression of AQP4 protein was noted in the duct cells from WT mice when compared to acinar cells. Pf did not show notable alterations between WT and AQP4 KO ducts. Carbachol elicited comparable secretory responses in ducts from both WT and KO animals. However, 8-bromo cAMP, VIP, and PHE stimulation resulted in decreased secretion in ducts from AQP4 KO LGs. Our findings underscore the functional relevance of AQP4 in the fluid production of mouse LG ducts. AQP4 seems to play different roles in fluid secretions elicited by different secretagogues. Specifically, cAMP-mediated, and adrenergic agonist-related secretions were reduced in AQP4 KO ducts.

Immunoglobulin G4-Related Disease Affecting the Tonsil: Case Report and Literature Review

Immunoglobulin G4-related disease (IgG4-RD) can involve multiple sites throughout the body. The most commonly affected sites in the head and neck are the salivary and lacrimal glands, respectively. Very few cases of IgG4-RD manifesting in the tonsils have been reported. Herein, we report the imaging findings of a 49-year-old female with pathologically confirmed IgG4-RD after a right-side tonsillectomy. The lesion showed diffuse homogeneous enhancement and appeared isointense and slightly hyperintense on T1- and T2-weighted magnetic resonance imaging, respectively. Diffusion restriction was also observed, which was considered to be due to the large number of IgG4-rich plasmacytes, and could vary depending on the degree of fibrosis. As distinguishing IgG4-RD from other diseases based solely on imaging is challenging, it is important to consider differential diagnosis, and clinical considerations are essential.

Clinical characteristics and treatment outcomes of patients with IgG4-positive ocular adnexal marginal zone B-cell lymphoma.

To explore the clinicopathological characteristics of immunoglobulin G4 (IgG4)-positive ocular adnexal marginal zone B-cell lymphoma (OAML) and associated patient treatment outcomes. Medical records from patients diagnosed with IgG4-positive OAML treated at the West China Hospital between January 2016 and August 2023 were retrospectively analyzed. This study included data from 22 patients (11 males, 11 females), aged between 36 and 83 years, with disease durations from 1 month to 30 years. Sixteen cases exhibited unilateral ocular involvement (ten left eyes, six right eyes), while six exhibited bilateral involvement. Common clinical symptoms included ocular masses, eyelid swelling, and proptosis, with the orbit and lacrimal gland being the most commonly impacted sites. Among the 22 patients, 13 who were clinically suspected of having IgG4-related ophthalmic disease (IgG4-ROD) underwent serum IgG4 testing pre-operatively, revealing elevated IgG4 levels in 11 of these patients. The use of computed tomography and magnetic resonance imaging facilitated the evaluation of the location and size of lesions. All 22 patients received surgical treatment. Subsequently, 14 of these patients underwent local radiotherapy, five received post-operative chemotherapy, and three were closely observed. The follow-up period of patients in this study was 3-77 months, with an average follow-up time of 36 months. Except for one patient who died of disease progression, all others showed favorable prognoses with significant improvements. These results support the classification of IgG4-positive OAML as a distinct OAML sub-type with clinical features that partially overlap with IgG4-ROD. Therefore, accurate differentiation between OAML and IgG4-ROD is imperative, necessitating timely surgical intervention and precise pathological diagnosis to prevent diagnostic errors and inappropriate treatment. Currently, no standardized treatments for IgG4-positive OAML exist, but our results suggest that standard OAML therapies are generally efficacious.

A study of clinical profile in patients of cataracts with pseudoexfoliation in rural populations of central India

Background Ophthalmologists deal with daily pseudoexfoliation (PXF) due to severe secondary glaucoma, which arises after cataract surgery. Cataracts with pseudoexfoliation are age-related and are associated with open-angle glaucoma. Therefore, pseudoexfoliation is expected to occur more frequently. Pseudoexfoliation is occasionally associated with the development of thick nuclear cataracts, which may make surgery challenging. risks of cataract extraction in patients with pseudoexfoliation include zonular weakness and inadequate pupillary dilation. This may cause vitreous loss, and intraoperative or postoperative lens displacement. It could also lead to a rise in postoperative intraocular pressure (IOP), progressing to long-term inflammation, phimosis of the capsular tissue, glaucoma, and surgical corneal decompensation. Recurrent secondary cataracts are typically caused by some remaining cortical tissue and decreased zonular support, which may lead to lens epithelial cell migration. Surgery for glaucoma and cataracts is complicated by the presence of pseudoexfoliative debris. Objectives To determine the prevalence of pseudoexfoliation in cataract patients visiting the ophthalmic OPD, AVBRH hospital, to locate patients with pseudoexfoliative cataracts, to evaluate their likelihood of progressing to open-angle glaucoma, and to examine the various ocular characteristics of these patients. Methodology The study participants will undergo ophthalmological examination after considering the inclusion and exclusion criteria. This examination will include sac syringing on the lacrimal gland, estimation of the highest corrected visual acuity, slit-lamp examination, application tonometer assessment of intraocular pressure (IOP), and fundus examination using an indirect ophthalmoscope. All individuals with cataracts visiting the ophthalmology department of AVBRH will be examined under a slit-lamp to determine the presence of pseudoexfoliation in the operating eye. Expected Results Hospital statistics from India indicated that the percentage of patients with pseudoexfoliation, in addition to cataracts, ranges from 1.87% to 13.5%.

Modulation of Decellularized Lacrimal Gland Hydrogel Biodegradation by Genipin Crosslinking.

Hydrogels derived from decellularized tissues are promising biomaterials in tissue engineering, but their rapid biodegradation can hinder in vitro cultivation. This study aimed to retard biodegradation of a hydrogel derived from porcine decellularized lacrimal glands (dLG-HG) by crosslinking with genipin to increase the mechanical stability without affecting the function and viability of lacrimal gland (LG)-associated cells. The effect of different genipin concentrations on dLG-HG stiffness was measured rheologically. Cell-dependent biodegradation was quantified over 10days, and the impact on matrix metalloproteinase (MMP) activity was quantified by gelatin and collagen zymography. The viability of LG epithelial cells (EpCs), mesenchymal stem cells (MSCs), and endothelial cells (ECs) cultured on genipin-crosslinked dLG-HG was assessed after 10days, and EpC secretory activity was analyzed by β-hexosaminidase assay. The 0.5-mM genipin increased the stiffness of dLG-HG by about 46%, and concentrations > 0.25mM caused delayed cell-dependent biodegradation and reduced MMP activity. The viability of EpCs, MSCs, and ECs was not affected by genipin concentrations of up to 0.5mM after 10days. Moreover, up to 0.5-mM genipin did not negatively affect EpC secretory activity compared to control groups. A concentration of 0.5-mM genipin increased dLG-HG stiffness, and 0.25-mM genipin was sufficient to prevent MMP-dependent degradation. Importantly, concentrations of up to 0.5-mM genipin did not compromise the viability of LG-associated cells or the secretory activity of EpCs. Thus, crosslinking with genipin improves the properties of dLG-HG for use as a substrate in LG tissue engineering.

Intraocular lacrimal gland choristoma

Ectopic lacrimal glands are rare, particularly intraocularly. We present the case of an infant who presented with a fleshy, vascular intraocular lesion and subsequently developed secondary glaucoma. The patient underwent primary enucleation, which was preferred over diagnostic biopsy due to the likelihood of malignancy and poor visual prognosis. Histology confirmed intraocular lacrimal gland choristoma. This case highlights the challenges in clinical diagnosis of intraocular lesions, and the potentially aggressive nature of benign tumours such as lacrimal gland choristomas.

Lacrimal sac diffuse large B-cell lymphoma presenting as sudden-onset binocular diplopia

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a prevalent subtype of non-Hodgkin lymphoma (NHL) affecting predominantly elderly individuals. Case description: A 68-year-old man with a history of hypertension, hyperlipidaemia and a small pituitary gland tumour presented with sudden-onset binocular diplopia and right-eye blurry vision. A magnetic resonance imaging (MRI) of the brain revealed enhancing soft tissue in the right superolateral orbit inseparable from the lacrimal gland, extending medially to the right superior rectus muscle and soft tissue. Further scanning showed widespread metastasis to the bilateral retroperitoneal lymph nodes, adrenal gland, spine and lymph nodes in the neck. A biopsy of the lacrimal gland confirmed DLBCL. Conclusion: Primary lacrimal gland DLBCL is a rare and delayed diagnosis that often stems from the resemblance of its clinical manifestations to more benign conditions such as dacryocystitis, dacryostenosis or mucocele. Timely recognition and accurate diagnosis are essential for initiating appropriate treatment and improving patient outcomes.

Radiological Imaging of the Lacrimal Gland in Sjogren’s Syndrome: A Systematic Review and Meta-Analysis

Purpose To critically appraise the evidence on the ability of the lacrimal gland ultrasonography (USG) or magnetic resonance imaging (MRI) to differentiate between Sjogren’s syndrome and non-Sjogren’s syndrome/healthy controls. Methods A systematic review and meta-analysis (based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) of online literature search was performed using PubMed, Scopus, and Cochrane databases. Cohort studies comparing the imaging features of the lacrimal glands of Sjogren’s syndrome with a control group were included. Quantitative synthesis was performed using the RevMan (Version 5.4.1). Results Six studies used USG as an imaging technique, and three used MRI for the lacrimal gland imaging. The lacrimal gland affected with Sjogren’s syndrome shows glandular heterogeneity on USG and MRI. Heterogeneity on USG had 6.18 times higher odds of the lacrimal gland being involved with Sjogren’s syndrome (95% CI, 3.31–11.55). Gland hyperechogenicity cannot reliably differentiate the glandular involvement in Sjogren’s syndrome. There is insufficient data for analysis on the gland size, hypoechoic areas, fibrous bands, and increased lacrimal artery resistance in Sjogren’s syndrome patients. Of the three MRI-based studies, reduced apparent diffusion coefficient and heterogeneity were the characteristics of Sjogren’s syndrome. Clinical parameters such as dry eye symptomatology and Schirmer values had variable associations with USG or MRI parameters. Ultrasonography parameters were no different between dry eye versus no dry eye in Sjogren’s syndrome patients, whereas small-sized glands had low Schirmer on MRI-based studies. Conclusion Glandular heterogeneity on USG is significantly associated with lacrimal gland involvement in Sjogren’s syndrome patients. However, the role of radiology in predicting lacrimal gland involvement is unclear as the evidence is insufficient and heterogeneous.

Diagnosis and Treatment of Lacrimal Gland Prolapse: A Narrative Review.

Lacrimal gland prolapse (LGP) is considered to be one of the causes for upper eyelid contour abnormality that should be recognized and treated properly to yield satisfactory outcomes in blepharoplasty. To describe current findings about the prevalence, pre- and intraoperative diagnosis of LGP and its treatment options. PubMed and Google Scholar were thoroughly searched for articles published describing the diagnosis and treatment of LGP. The reported prevalence of LGP by various authors varies between 10 and 60% based on their preoperative or intraoperative reports. Techniques such as dacryoadenopexy, modified dacryoadenopexy, and dacryoplasty have been described to secure the prolapsed lacrimal gland back into its original position. Additionally, creating a Whitnall's barrier has also been suggested as a method to reposition the gland. While all these surgical procedures have shown promising immediate results, there is a lack of published data on their long-term outcomes. Diagnosis and proper treatment of LGP could enhance the cosmetic results of upper eyelid blepharoplasty. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Isolated ocular sarcoidosis

A rare clinical case of a patient with isolated sarcoidosis of the eyes is presented. Sarcoidosis is a polyethological disease, the morphological feature of which is the formation of epithelioid cell granulomas in various organs and tissues, which is accompanied by a violation of their structure and function. Both congenital and adaptive immune systems are involved in the pathogenesis of sarcoidosis, with damage to lymph nodes, lungs, skin, organ of vision, etc. Risk factors for the development of sarcoidosis have not been definitively established. Environmental factors and genetic predisposition play a crucial role in the development of the disease. The above clinical observation demonstrates the polymorphism of the clinical picture of isolated ocular sarcoidosis. In addition to standard ophthalmic examination methods, the genetic method of reverse transcription and quantitative polymerase chain reaction (RT-PCR, English qRT-PCR) was also used to determine the expression profile of signature microRNAs as potential diagnostic markers of sarcoidosis of the organ of vision.An increase in the expression level of hsa-miR-455-3p, hsa-miR-4663, hsamiR68063p, hsa-miR-450b-5p, hsa-miR-6716-3p, hsa-miR-5000-5p, hsa-miR150-5p can be considered as potential diagnostic biomarkers of sarcoid lesion of eye structures. With sarcoidosis, the involvement of the lacrimal gland is possible. In the presented clinical observation, this was indicated by the results of a functional examination, sonographic signs: revealed multiple linear tubular hyperechoic structures and a decrease in blood flow velocity in the ocular and lacrimal arteries, as well as an increase in the expression activity of hsa-miR150-5p (p < 0.05). In order to prevent possible damage to the ocular surface due to the development of lacrimal gland dysfunction, it is advisable to prescribe local tear replacement therapy with hyaluronic acid preparations. Such effective drugs include tear substitutes of the Optinol® line: “Optinol® Express Moisture” and “Optinol® Deep Moisture”.

Long Non-Coding RNAs in Sjögren's Disease.

Sjögren's disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic pain. Chronic inflammation of the salivary and lacrimal glands, auto-antibody formation, and extra-glandular manifestations occur in subsets of patients with SjD. An aberrant expression of long, non-coding RNAs (lncRNAs) has been described in many autoimmune diseases, including SjD. Here, we review the current literature on lncRNAs in SjD and their role in regulating X chromosome inactivation, immune modulatory functions, and their potential as biomarkers.

ΔNp63 regulates Sfrp1 expression to direct salivary gland branching morphogenesis.

Branching morphogenesis is a complex process shared by many organs including the lungs, kidney, prostate, as well as several exocrine organs including the salivary, mammary and lacrimal glands. This critical developmental program ensures the expansion of an organ's surface area thereby maximizing processes of cellular secretion or absorption. It is guided by reciprocal signaling from the epithelial and mesenchymal cells. While signaling pathways driving salivary gland branching morphogenesis have been relatively well-studied, our understanding of the underlying transcriptional regulatory mechanisms directing this program, is limited. Here, we performed in vivo and ex vivo studies of the embryonic mouse submandibular gland to determine the function of the transcription factor ΔNp63, in directing branching morphogenesis. Our studies show that loss of ΔNp63 results in alterations in the differentiation program of the ductal cells which is accompanied by a dramatic reduction in branching morphogenesis that is mediated by dysregulation of WNT signaling. We show that ΔNp63 modulates WNT signaling to promote branching morphogenesis by directly regulating Sfrp1 expression. Collectively, our findings have revealed a novel role for ΔNp63 in the regulation of this critical process and offers a better understanding of the transcriptional networks involved in branching morphogenesis.

A Rabbit Dry Eye Model Induced by Subcutaneous Scopolamine

Purpose To establish and characterize a dry eye model in New Zealand rabbits by subcutaneous injections of scopolamine hydrobromide (SCOP). Methods Twenty New Zealand male rabbits were injected subcutaneously SCOP for 14 consecutive days; subcutaneous saline was used as a negative control. The correlated clinical parameters of ocular surface dryness were detected in vivo using tear secretion and corneal fluorescein staining. The expression of IL-1β and TNF-α on the ocular surface and in lacrimal glands were analyzed by real-time PCR and western blot on the 14th day. The expression of Mucin-5 subtype AC (MUC5AC) was detected by Immunofluorescence staining in conjunctival tissue. Results The SCOP-treated rabbits exhibited significantly decreased aqueous tear secretion and increased corneal fluorescein staining scores over time. Both the mRNA expression levels and the protein expression levels of IL-1β and TNF-α were significantly increased after SCOP treatment compared with those after saline treatment. The loss of conjunctival MUC5AC was found in the SCOP-injected rabbits. Some infiltrated inflammatory cells and atrophic acinar cells were observed in the lacrimal gland after SCOP treatment. The disordered structures of the ocular surface and lacrimal glands were also observed. Conclusions This study showed that repeated subcutaneous SCOP injections successfully elicited some of the typical dry eye symptoms commonly seen in humans.

Effects of age on lacrimal gland bioactive lipids

PurposePolyunsaturated fatty acids (PUFA) are a source of bioactive lipids regulating inflammation and its resolution. MethodsChanges in PUFA metabolism were compared between lacrimal glands (LGs) from young and aged C57BL/6 J mice using a targeted lipidomics assay, as was the gene expression of enzymes involved in the metabolism of these lipids. ResultsGlobal reduction in PUFAs and their metabolites was observed in aged LGs compared to young controls, averaging between 25 and 66 % across all analytes. ꞷ-6 arachidonic acid (AA) metabolites were all reduced in aged LGs, where the changes in prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) were statistically significant. Several other 5-lipoxygenase (5-LOX) mediated metabolites were significantly reduced in the aged LGs, including D-series resolvins (e.g., RvD4, RvD5, and RvD6). Along with the RvDs, several ꞷ-3 docosahexaenoic acid (DHA) metabolites such as 14-HDHA, neuroprotectin D1 (NPD1), Maresin 2 (MaR2), and MaR 1 metabolite (22-COOH-MaR1) were significantly reduced in aged LGs. Similarly, ꞷ-3 eicosapentaenoic acid (EPA) and its metabolites were significantly reduced in aged LGs, where the most significantly reduced was 18-HEPE. Using metabolite ratios (product:precursor) for specific metabolic conversions as surrogate enzymatic measures, reduced 12-LOX activity was identified in aged LGs. ConclusionIn this study, global reduction of PUFAs and their metabolites was found in the LGs of aged female C57BL/6 J compared to young controls. A consistent reduction was observed across all detected lipid analytes except for ꞷ-3 docosapentaenoic acid (DPA) and its special pro-resolving mediator (SPM) metabolites in aged mice, suggesting an increased risk for LG inflammation.

Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblastoma used in the PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06)

BackgroundThe PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. MethodsA suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). ResultsMedian DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1–391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5–142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00–0.69) and the right lacrimal gland (median 0.59, range 0.42–0.78). ConclusionsThe deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registrationNCT05871021