Anti-carbonic Anhydrase Research Articles

Imaging in Renal Cell Carcinoma Detection.

Imaging in renal cell carcinoma (RCC) is a constantly evolving landscape. The incidence of RCC has been rising over the years with the improvement in image quality and sensitivity in imaging modalities resulting in "incidentalomas" being detected. We aim to explore the latest advances in imaging for RCC. A literature search was conducted using Medline and Google Scholar, up to May 2024. For each subsection of the manuscript, a separate search was performed using a combination of the following key terms "renal cell carcinoma", "renal mass", "ultrasound", "computed tomography", "magnetic resonance imaging", "18F-Fluorodeoxyglucose PET/CT", "prostate-specific membrane antigen PET/CT", "technetium-99m sestamibi SPECT/CT", "carbonic anhydrase IX", "girentuximab", and "radiomics". Studies that were not in English were excluded. The reference lists of selected manuscripts were checked manually for eligible articles. The main imaging modalities for RCC currently are ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Contrast-enhanced US (CEUS) has emerged as an alternative to CT or MRI for the characterisation of renal masses. Furthermore, there has been significant research in molecular imaging in recent years, including FDG PET, PSMA PET/CT, 99mTc-Sestamibi, and anti-carbonic anhydrase IX monoclonal antibodies/peptides. Radiomics and the use of AI in radiology is a growing area of interest. There will be significant change in the field of imaging in RCC as molecular imaging becomes increasingly popular, which reflects a shift in management to a more conservative approach, especially for small renal masses (SRMs). There is the hope that the improvement in imaging will result in less unnecessary invasive surgeries or biopsies being performed for benign or indolent renal lesions.

Oxidative Stress and Anti-Carbonic Anhydrase Antibody Levels in Early Preeclampsia: A Clinical Investigation

Objective: Preeclampsia (PE) is a dangerous condition that affects 3–5% of pregnancies and has a substantial risk of death and morbidity for both mothers and newborns. The processes behind the etiology of PE are not entirely known, despite the fact that it is the primary cause of illness and death among mothers globally. In order to further understand the correlations between these parameters, this study will look at the levels and presence of anti-carbonicianhydrase (CA) I and II antibodies, total oxidanticapacity (TOC), total antioxidanticapacity (T-AOC), and malondialdehyde (MDA) in early PE. Methods: The research analyzed 30 pregnant women with early PE and 30 normal pregnant women as the control group. Serumxlevels of anti-CAiI (pg/mL), anti-CAxII (ng/mL), MDA (nmol/mL), TOS (U/mL), T-AOC (U/mL) were measured and compared between the two groups. Results: Significant variations were noted in the amount of anti-CA I, anti-CA II, MDA, TOS, and T-AOC (both p

Characterization of autoimmune eye disease in association with Down's syndrome.

Autoimmunity and deficiency of the transcription factor autoimmune regulator protein (AIRE) are known associations with Down syndrome (DS). Lack of AIRE abrogates thymic tolerance. The autoimmune eye disease associated with DS has not been characterized. We identified a series of subjects with DS (n = 8) and uveitis. In three consecutive subjects, we tested the hypothesis that autoimmunity to retinal antigens might be a contributing factor. This was a multicentred, retrospective case series. Deidentified clinical data of subjects with both DS and uveitis were collected via questionnaire by uveitis-trained ophthalmologists. Anti-retinal autoantibodies (AAbs) were detected using an Autoimmune Retinopathy Panel tested in the OHSU Ocular Immunology Laboratory. We characterized eight subjects (mean age 29 [range, 19-37] years). The mean age of detected uveitis onset was 23.5 [range, 11-33] years. All eight subjects had bilateral uveitis (p < 0.001 based on comparison to published university referral patterns), with anterior and intermediate uveitis found in six and five subjects respectively. Each of three subjects tested for anti-retinal AAbs was positive. Detected AAbs included anti-carbonic anhydrase II, anti-enolase, anti-arrestin, and anti-aldolase. A partial deficiency in the AIRE on chromosome 21 has been described in DS. The similarities in the uveitis presentations within this patient group, the known autoimmune disease predisposition in DS, the recognized association of DS and AIRE deficiency, the reported detection of anti-retinal antibodies in patients with DS in general, and the presence of anti-retinal AAbs in three subjects in our series supports a causal association between DS and autoimmune eye disease.

Anti-Carbonic Anhydrase Goldbodies by Conformational Reconstruction of the Complementary-Determining Regions of Phage-Displayed Antibodies.

It has been demonstrated that the main complementary-determining region (CDR)of antibodies could be grafted onto gold nanoparticles (AuNPs) to produce artificial antibody, dubbed Goldbody. Goldbody maintains the same binding specificityas the original antibody, but has better stability. However, the current design of Goldbodies is mainly based on the structures of antibody-antigen complexes. To extend this promising technique to the majority of antibodies whose complexes with the corresponding antigens are not structurally solved, herein, two anti-carbonic anhydrase (CA) antibodies screened by phage display were chosen to create anti-CA Goldbodies. One of the anti-CA antibodies, cAb-CA05, has a known complex structure with CA; but the other, cAb-CA06, does not. By conformational reconstruction of the CDR3 of cAb-CA06, which is identified by sequence alignment, as well as the CDR3 of cAb-CA05, two anti-CA Goldbodies have been created. Interestingly, our results show the two Goldbodies can bind to CA simultaneously, unambiguously indicating their binding sites on CA are far away. As the CDR3 is the major binding unit for many antibodies, which can be reliably predicted by sequence alignment, it could be used as a general strategy to develop artificial antibodies by directly grafting and conformationally reconstructing the predicted CDR3 of antibodies.

Anti-carbonic anhydrase II antibody reflects urinary acidification defect especially in proximal renal tubules in patients with primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmue disease featured by excessive autoantibody production. It has been demonstrated that anti-carbonic anhydrase II (anti-CA II) antibody is correlated with renal tubular acidosis in pSS; however, no further details about urinary acidification defect have been reported, and the antibody's relationship with other organ impairments remains unknown. This case-control study aimed to examine anti-CA II antibody levels in relation to various systemic complications in pSS, and evaluate its potential role as a organ-specific biomarker in a Chinese cohort. Serum anti-CA II antibody levels were determined using ELISA in 123 patients with pSS and 72 healthy controls. The medical records of the patients were collected, and the correlation between serum anti-CA II antibody and clinical/immunological parameters was investigated. Serum anti-CA II antibody level and its positive rate were significantly increased in pSS patients compared with controls, and ANA-positive patients presented even higher titers of the antibody. In anti-CA II positive group, remarkably higher urine pH and bicarbonate, as well as lower urine titratable acid and serum potassium were observed, which indicated renal tubular acidification dysfunction both involving bicarbonate reabsorption and acid secretion. In addition, platelet count and complement 3, complement 4 levels decreased, whereas serum IgG, IgA and γ-globulin levels increased notably in accord with a higher EULAR SS disease activity index score in these patients. Further analysis showed that anti-CA II antibody was most elevated in patients with defect in bicarbonate reabsorption, reflecting proximal renal tubular injury, rather than in patients with distal renal tubular acidosis as previously reported. In conclusion, anti-CA II antibody reflects renal (especially proximal renal tubular) and hematologic impairment as well as increased disease activity in pSS. It may act as a serum biomarker of systemic damage of pSS.

Case-Control Study Examining the Composition of the Gut Microbiome in Individuals With and Without Immune-Mediated Dry Eye.

Gut microbiome alterations have been associated with various autoimmune diseases. There are limited data, however, on relationships between gut dysbiosis and immune-related dry eye (DE). Our aim was to compare the gut microbiome composition of individuals with early and late markers of Sjögren syndrome (SS) with controls without DE. We compared 20 individuals with positive early markers [antisalivary protein 1 (SP1), antiparotid secretory protein (PSP), anticarbonic anhydrase 6 (CA6) IgG, IgA, and IgM, n = 19)], or late markers (anti-Ro/SS-A and anti-La/SS-B, n = 1) of SS with no comorbid autoimmune diagnoses and 20 age-matched and sex-matched controls. Collected stool samples underwent deep RNA sequencing. The main outcomes measured included gut microbiome composition and diversity. A total of 20 cases [Dry Eye Questionnaire-5 15.2 ± 3.4, Ocular Surface Disease Index 55.1 ± 22.8, and Schirmer 7.1 ± 5.2 mm] were compared with 20 controls (Dry Eye Questionnaire-5 4.8 ± 3.8, Ocular Surface Disease Index 14.2 ± 12.3, and Schirmer 20.4 ± 9.2 mm). No differences were observed in α-diversity ( P = 0.97) or overall community structure ( P = 0.62). Between groups, 32 species were differentially abundant ( P < 0.01). Among cases, 27 were relatively more abundant, including 10 Lactobacillus and 4 Bifidobacterium species. A relative depletion of 5 species was found in cases compared with controls, notably Fusobacterium varium and Prevotella stercorea . Differences in gut microbiome composition were found in individuals with mostly early markers of SS compared with controls. However, their clinical significance to DE manifestations remains unclear. Further studies are needed to elucidate the role of gut dysbiosis on immune dysregulation and disease activity in the various forms of immune-mediated DE.

Anti-retinal Antibodies in Sarcoidosis

ABSTRACT Purpose To measure, characterize, and evaluate the clinical significance of anti-retinal antibodies in patients with sarcoid uveitis. Subjects/Methods Prospective study of anti-retinal antibodies in 45 patients with biopsy-proven sarcoidosis (25 with and 20 without uveitis). Results were compared with patients with confirmed infectious uveitis (n = 40) and non-infectious uveitis (n = 40). Results Among sarcoidosis patients, anti-retinal antibodies were positive in 23/25 patients with uveitis and in 15/20 without uveitis [P = ns]. The most common antigens recognized were carbonic anhydrase II (14/23) and α-enolase (6/23). Anti-carbonic anhydrase II autoantibodies were infrequently detected in sarcoidosis patients without uveitis (2 out 15, P < .001), in patients with infectious uveitis (1 out 18, P < .001), and in patients with non-infectious uveitis (8 out 37, P < .001). Conclusions Anti-retinal antibodies recognizing carbonic anhydrase II are common in sarcoid uveitis. Although not fully sensitive and specific, they might be a useful non-invasive diagnostic tool for the diagnosis of sarcoid uveitis.

Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells.

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to ≅108 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8α/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a ≅107 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 107 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

Sulfonamide drugs: structure, antibacterial property, toxicity, and biophysical interactions.

Sulfonamide (or sulphonamide) functional group chemistry (SN) forms the basis of several groups of drug. In vivo sulfonamides exhibit a range of pharmacological activities, such as anti-carbonic anhydrase and anti-t dihydropteroate synthetase allowing them to play a role in treating a diverse range of disease states such as diuresis, hypoglycemia, thyroiditis, inflammation, and glaucoma. Sulfamethazine (SMZ) is a commonly used sulphonamide drug in veterinary medicine that acts as an antibacterial compound to treat livestock diseases such as gastrointestinal and respiratory tract infections. Sulfadiazine (SDZ) is another frequently employed sulphonamide drug that is used in combination with the anti-malarial drug pyrimethamine to treat toxoplasmosis in warm-blooded animals. This study explores the research findings and the work behaviours of SN (SMZ and SDZ) drugs. The areas covered include SN drug structure, SN drug antibacterial activity, SN drug toxicity, and SN environmental toxicity.

Targeted PET/CT imaging for clear cell renal cell carcinoma with radiolabeled antibodies: recent developments using girentuximab.

Conventional imaging is unable to differentiate clear cell renal cell carcinoma (ccRCC) from other more indolent and benign renal tumors. Positron emission tomography/computed tomography (PET/CT) using radiolabeled antibodies may aid in detecting both localized and metastatic ccRCC. The purpose of this review is to summarize recent literature regarding the use of radiolabeled antibodies for imaging of ccRCC. Two recent studies evaluated the use of radiolabeled anticarbonic anhydrase IX antibody girentuximab for the imaging of ccRCC. PET/CT with 89zirconium-labeled girentuximab (89Zr-girentuximab PET/CT) was used to guide clinical decision making in 16 patients with localized disease. It had a high specificity for detecting ccRCC with 6/6 resected lesions with uptake proven to be ccRCC, all lesion without uptake showed to be indolent during follow-up. Clinical management was changed in 36% (5/14) of patients with the metastatic disease based on outcomes of the scan. Furthermore, in 42 patients 89Zr-girentuximab PET/CT combined with CT outperformed CT alone or combined with 18F fludeoxyglucose PET for detection of metastasis. 89Zr-girentuximab PET/CT has the ability to diagnose ccRCC in localized disease. In metastatic disease, it enables the differentiation of ccRCC from non-ccRCC cancers and the evaluation of disease extent. 89Zr-girentuximab PET/CT diagnostic accuracy is currently evaluated in a multicenter phase III trial.

Immunotherapy with Immunocytokines and PD-1 Blockade Enhances the Anticancer Activity of Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX

Small molecule-drug conjugates (SMDCs) represent an alternative to conventional antitumor chemotherapeutic agents, with the potential to improve the therapeutic window of cytotoxic payloads through active delivery at the site of the disease. In this article, we describe novel combination therapies consisting of anti-carbonic anhydrase IX SMDCs combined with different immunomodulatory products. The therapeutic effect of the SMDCs was potentiated by combination with PD-1 blockade and with tumor-homing antibody-cytokine fusions in mouse models of renal cell carcinoma and colorectal cancer. The combination with L19-IL12, a fusion protein specific to the alternatively spliced EDB domain of fibronectin containing the murine IL12 moiety, was also active against large established tumors. Analysis of the microscopic structures of healthy organs performed 3 months after tumor eradication confirmed absence of pathologic abnormalities in the healthy kidney, liver, lung, stomach, and intestine. Our findings may be of clinical significance as they provide motivation for the development of combinations based on SMDCs and immunotherapy for the treatment of renal cell carcinoma and hypoxic tumors.

Anti-retinal autoantibodies in myopic macular degeneration: a pilot study

AimThe aim of this study is to evaluate the frequency and types of anti-retinal autoantibodies (ARAs) in highly myopic patients and to explore any association between ARAs and the severity of myopic macular degeneration (MMD).MethodsThis was a clinic-based study of 16 patients with high myopia (spherical equivalent worse than −6 dioptres or axial length (AL) ≥ 26.5 mm) recruited from the High Myopia clinic of the Singapore National Eye Centre. MMD was graded from fundus photographs according to the Meta-analysis for Pathologic Myopia (META-PM) classification. Severe MMD was defined as META-PM category 3 or 4. AL and logarithm of the minimal angle of resolution (logMAR) best corrected visual acuity (BCVA) were measured. Sera were obtained from subjects and analysed for the presence of ARAs with the western blot technique.ResultsThe mean AL was significantly longer in patients with severe MMD (n = 8) than those without severe MMD (n = 8) (31.50 vs. 28.51, p = 0.005). There was at least one ARA identified in all patients. The most common ARA was anti-carbonic anhydrase II (anti-CAII), present in nine patients (56.3%). Anti-CAII was detected in more patients with severe MMD than those without (75 vs. 37.5%, p = 0.32). LogMar BCVA was also worse in subjects with anti-CAII (0.5 ± 0.38 vs. 0.22 ± 0.08, p = 0.06). The number of ARAs significantly correlated with increasing AL (r = 0.61, p = 0.012).ConclusionsARAs are prevalent in patients with high myopia, and this increases with increasing AL. In particular, anti-CAII antibodies were highly prevalent in patients with severe MMD, suggesting that ARAs may be associated with MMD. Further studies are necessary to confirm these observations in larger cohorts.

Phthalocyanine complexes with (4-isopropylbenzyl)oxy substituents: preparation and evaluation of anti-carbonic anhydrase, anticholinesterase enzymes and molecular docking studies

In this study, the preparation, aggregation behavior and investigation of carbonic anhydrase and cholinesterase enzyme inhibition features of non-peripherally (4-isopropylbenzyl)oxy-substituted phthalocyanines (4–6) are reported for the first time. The chemical structures of these new phthalocyanines were elucidated by UV-Vis (ultraviolet-visible), FT-IR (Fourier transform infrared spectrometry), NMR (nuclear magnetic resonance) and MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry. The substitution of 4-isopropylbenzyl)oxy groups benefits a remarkable solubility and redshift of the phthalocyanines Q-band. Also, these complexes were tested against some enzymes such as butyrylcholinesterase enzyme, human carbonic anhydrase I and II isoforms and acetylcholinesterase enzyme. The phthalocyanine complexes showed Ki values of in the range of 478.13 ± 57.25–887.25 ± 101.20 µM against hCA I, 525.16 ± 45.87–921.14 ± 81.25 µM against hCA II, 68.33 ± 9.13–201.15 ± 35.86 µM against AChE and 86.25 ± 13.65–237.54 ± 24.7 µM against BChE. Molecular docking studies were performed to investigate the binding modes and interaction energies of the (2–6) complexes with the hCA I (PDB ID:1BMZ), hCA II (PDB ID:2ABE), AChE (PDB ID:4EY6) and BChE (PDB ID:2PM8).

Targeted and redox-responsive drug delivery systems based on carbonic anhydrase IX-decorated mesoporous silica nanoparticles for cancer therapy

In this work, we developed a new antibody-targeted and redox-responsive drug delivery system “MSNs-CAIX” by binding the anti-carbonic anhydrase IX antibody (A-CAIX Ab) on the surface of mesoporous silica nanoparticles (MSNs) via disulfide linkages. The design of the composite particles “MSNs-CAIX” involved the synthesis and surface functionalization with thiol groups, 2,2′-dipyridyl disulfide and CAIX antibody. In vitro, CAIX capping the doxorubicin hydrochloric (DOX)-loaded nanoparticles (DOX@MSNs-CAIX) exhibited effectively redox-responsive release in the presence of glutathione (GSH) owing to the cleavage of the disulfide bond. Compared with CAIX negative Mef cells (mouse embryo fibroblast), remarkably more DOX@MSNs-CAIX was internalized into CAIX positive 4T1 cells (mouse breast cancer cells) by receptor-mediation. Tumor targeting in vivo studies clearly demonstrated DOX@MSNs-CAIX accumulated in tumors and induced more tumor cells apoptosis in 4T1 tumor-bearing mice. With great potential, this drug delivery system is a promising candidate for targeted and redox-responsive cancer therapy.

Serum levels of anti-carbonic anhydrase antibodies and erythrocyte oxidative stress markers in endometriosis

Aim: To evaluate the serum levels of anti-carbonic anhydrase I-II antibodies and erythrocyte oxidative stress markers in endometriosis. Method: This case-control laboratory investigation was performed in the obstetrics and gynecology department of a tertiary center. Serum anti-carbonic anhydrase I and II antibodies and erythrocyte oxidative stress markers (superoxide dismutase, malondialdehyde, glutathione peroxidase and catalase) were compared with control group (n = 30) in the endometriosis group (n = 33). Correlation between carbonic anhydrase autoantibodies and oxidative stress markers were tested. Results: Serum levels of anti-carbonic anhydrase II antibodies were found to be significantly increased in the endometriosis group compared to controls. The erythrocyte antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase and catalase) and malondialdehyde levels in erythrocytes were increased in endometriosis group; but only glutathione peroxidase activity and malondialdehyde levels were significantly higher in endometriosis group. No correlation was detected between anti-carbonic anhydrase antibodies and oxidative stress markers. Conclusions: Our results indicate that erythrocyte oxidative stress and anti-carbonic anhydrase antibodies may be involved in the pathophysiology of endometriosis.

Mesenchymal stem cell transplantation attenuates growth of chemotherapy treated oral squamous cell carcinoma in an animal model.

Recent studies have demonstrated mesenchymal stem cell migration toward tumor locations. When applied locally, MSCs interact with the locally residing host cells. The mechanisms behind this are still unclear. We aimed to detect the possible action mechanisms of MSCs on the in vivo growth of primary human oral squamous cell carcinoma. In mouse model of OSSC, chemotherapy with Cisplatin was done beginning from 9day of tumor visualization. 3weeks after tumor cell injection cultivated MSCs were administrated in tail vein or directly intra-tumorally. Animals underwent surveillance and afterward were sacrificed. Tumor growth was measured. MSCs biodistribution was assessed with bioluminescent analysis. Tumor tissues were tested morphologically and immunohistochemically for angiogenesis, hypoxia status, and cell apoptosis. In the group treated with Cisplatin in combination with mesenchymal stem cell injection, the average size of the tumor was 98.9±7.65mm3 . In the experimental group, tumor tissues were less outlined and the presence of necrotic areas and connective tissue basal layers was detected. Immunohistochemical surveys with CD31 and anti-carbonic anhydrase 9 demonstrated strongly developed micro-vessel structures and small isles of hypoxia in the tumor tissues. TUNEL assay revealed in the same group that tumor tissues were mostly comprised of apoptotic cells. Viable cell communities presented as small isles. The study demonstrates that intra-tumorally injected MSCs, combined with Cisplatin, leads to a minimal hypoxia status and increased apoptotic activity in tumor tissues, compared with the control group. This finding can be explained with better distribution of Cisplatin due to increased angiogenesis.

Pharmacophores Modeling in Terms of Prediction of Theoretical Physicochemical Properties and Verification by EXPERIMENTAL correlations of Carbacylamidophosphates (CAPh) and Sulfanylamidophosphates (SAPh) Tested as New Carbonic Anhydrase Inhibitors.

The function of Carbonic anhydrase is to facilitate the physiological process i.e. interconversion of CO2 to HCO3 - by hydration. Carbonic anhydrase enzyme plays a vital role in different physiological processes to regulate pH as well as regulate the inner environment of CO2 and secretion of electrolytes. Six representatives of amidophosphate derivatives (L1-L6) were synthesized and evaluated for their biological activities against carbonic anhydrase enzyme. Out of six derivatives, L1 (IC50 = 12.5 ± 1.35 µM), and L2 (IC50 = 3.12 ± 0.45 µM) showed potent activity against BCA-II. While (L3, L4 and L5) showed weak inhibitory activity with IC50 values of 24.5 ± 2.25, 55.5± 1.60, and 75.5 ± 1.25 µM, respectively and were found to be weak inhibitors of carbonic anhydrase as compared to acetazolamide (IC50 =0.12± 0.03µM), used as standard inhibitor. A computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been expanded for the determination of physicochemical parameters governing the bioactivity amidophosphate derivatives (L1-L6) containing (O1 --- O2) pharmacophore site. The six compounds (L1-L6) analyzed here were previously experimentally and now virtually screened for their anti-carbonic anhydrase activity. The highest anti-carbonic anhydrase activity was obtained for compound L2, which exhibited excellent bioactivity (% of inhibition = 95%), comparable to acetazolamide (% of inhibition = 89%). The compound L3 represents increased activity as compared to its analogues (L4-L6). The increase of bioactivity from L3 to L4-L6 could be attributed to the presence of a minimum of steric effect of substituents of P=O moiety which plays a decisive template part in the organization of anti-carbonic anhydrase (O1---O2) phramacophore site. Moreover, it is inexpensive, has little side effects and possible inclusions in selective anti-carbonic anhydrase agents design.

Clinical Correlations of Novel Autoantibodies in Patients with Dry Eye.

Background Diagnostic criteria for Sjögren's syndrome (SS) are continually being updated in pursuit of more precise and earlier diagnosis to prevent its complications. Owing to the high rate of false negative traditional serological markers, the need for better serological testing remains. Objective To investigate the clinical significance of three recently discovered novel autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6), and anti-parotid secretory protein (PSP), in a cohort of dry eye patients with suspected underlying inflammatory/autoimmune disease. Methods Medical records of 136 patients with a primary diagnosis of dry eye who underwent laboratory testing between April 2014 and July 2017 were reviewed retrospectively. Data regarding demographic information, ocular and systemic symptoms, previous medical diagnoses, serological test results, and minor salivary gland biopsy results were collected. Dry eye evaluations included tear osmolarity, Schirmer test without anesthesia, conjunctival lissamine green staining, and corneal fluorescein staining in the order listed here. Results Of the 136 patients, 9 (9/136, 6.6%) presented with a history of SS, and 9 additional patients (9/127, 7%) received a new diagnosis of SS as a result of evaluations. Fifty-six patients (56/136, 41%) tested positive for at least one of the novel autoantibodies. Fifty-four percent (6/11) of patients with primary SS who underwent the novel serological testing had a positive anti-PSP. Of those, 2 (2/11, 18%) had negative traditional serology and had to undergo minor salivary gland biopsy for definitive diagnosis. Anti-CA6 was associated with increased corneal and conjunctival staining after adjusting for age, sex, and other serologic markers (HR = 1.5, 95% CI = 1.20-1.97, and p = 0.009 and HR = 1.4, 95% CI = 1.04-1.76, and p = 0.02, respectively). Conclusions This cross-sectional study demonstrated that anti-CA6 is seen in patients with severe aqueous-deficient dry eye. Whether these patients have an early stage of SS or a different type of autoimmune condition may be determined through longitudinal studies.

Are Anti-Retinal Autoantibodies a Cause or a Consequence of Retinal Degeneration in Autoimmune Retinopathies?

Autoantibodies (AAbs) against various retinal proteins have been associated with vision loss in paraneoplastic and non-paraneoplastic autoimmune retinopathies (AR). There are two major paraneoplastic syndromes associated anti-retinal AAbs, cancer-associated retinopathy (CAR), and melanoma-associated retinopathy. Some people without a cancer diagnosis may present symptoms of CAR and have anti-retinal AAbs. The etiology and pathogenesis of those entities are not fully understood. In this review, we provide evidence for the role of AAbs in retinal death and degeneration. Studies of epitope mapping for anti-recoverin, anti-enolase, and anti-carbonic anhydrase II revealed that although patients’ AAbs may recognize the same retinal protein as normal individuals they bind to different molecular domains, which allows distinguishing between normal and diseased AAbs. Given the great diversity of anti-retinal AAbs, it is likely some antibodies have greater pathogenic potential than others. Pathogenic, but not normal antibodies penetrate the target cell, reach their specific antigen, induce apoptosis, and impact retinal pathophysiology. Photoreceptors, dying by apoptosis, induced by other than immunologic mechanisms produce substantial amounts of metabolic debris, which consequently leads to autoimmunization and enhanced permeability of the blood–retinal barrier. AAbs that were made as a part of anti-cancer response are likely to be the cause of retinal degeneration, whereas others, generated against released antigens from damaged retina, contribute to the progression of retinopathy. Altogether, AAbs may trigger retinal degeneration and may also exacerbate the degenerative process in response to the release of sequestered antigens and influence disease progression.

Dual-ligand modified liposomes provide effective local targeted delivery of lung-cancer drug by antibody and tumor lineage-homing cell-penetrating peptide

The abilities of a drug delivery system to target and penetrate tumor masses are key factors in determining the system’s chemotherapeutic efficacy. Here, we explored the utility of an anti-carbonic anhydrase IX (anti-CA IX) antibody and CPP33 dual-ligand modified triptolide-loaded liposomes (dl-TPL-lip) to simultaneously enhance the tumor-specific targeting and increase tumor cell penetration of TPL. In vitro, the dl-TPL-lip increased the cytotoxicity of TPL in CA IX-positive lung cancer cells, which showed tunable size (137.6 ± 0.8 nm), high-encapsulation efficiency (86.3 ± 2.6%) and sustained release. Dl-TPL-lip significantly improved the ability of liposomes to penetrate 3 D tumor spheroids and exhibited a superior inhibiting effect. Furthermore, pharmacokinetic studies in rats that received TPL liposomal formulations by endotracheal administration showed a reduced concentration of TPL (17.3%–30.6% compared to free TPL) in systemic circulation. After pulmonary administration in orthotopic lung tumor-bearing mice, dl-TPL-lip significantly enhanced TPL anti-cancer efficacy without apparent systemic toxicity. This dual-ligand modified liposomal vehicle presents a potential system for localized and targeted delivery of anti-cancer drugs to improve their efficacy.