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Introduction: In this work, we provide a detailed characterization of a rare complication-subconjunctival cyst formation after strabismus surgery-in a large German cohort., Methods: We conducted a retrospective analysis of 822 consecutive patients who underwent strabismus surgery between 2015 and 2022. The patients received comprehensive eye and orthoptic examinations preoperatively, at 1 day, and at 3 months postoperatively. Cysts were analyzed with slit-lamp examination, anterior segment optical coherence tomography (AS-OCT), and histopathological subsumption., Results: Nineteen cases of postoperative cysts were observed (2.3%), 12 of which underwent surgical revision. Clinical evaluation including slit-lamp and AS-OCT as well as histological analysis resulted in a classification of three types of cysts: type 1, which is a single hyporeflective cyst, type 2, which is a multilobular hyporeflective cyst, and type 3, a dense hyperreflective granulomatous-like cyst. Eta (η) correlation ratio analysis could show a correlation between time of clinical appearance and type of cyst (Eta = 0.63). Most cysts developed within 20 days after surgery. Not only did cysts more frequently affect the medial rectus muscle, which in most cases underwent a shortening procedure (11/19 tucks, 4/19 resections) for intermittent exotropia (X(T)), but the cyst also formed earlier than in the lateral rectus muscle (Eta = 0.45). No correlation could be shown between the type of surgical procedure and time of cyst occurrence (Eta = 0.1). Patient age and cyst type correlated strongly (Eta = 0.47). The underlying type of strabismus did not correlate with the type of cyst observed., Conclusions: Our cases showed a strong positive correlation to the type of strabismus (X(T)), age (young patients), and the procedure (tuck/resection). We introduce a grading system for postoperative cysts after strabismus surgery, complementing histopathology and slit-lamp aspects with AS-OCT information., (© 2023. The Author(s).)

This study evaluates the long-term effects of selective retina therapy (SRT) on the retinal pigment epithelium (RPE) and neuroretina in patients with central serous chorioretinopathy. SRT was performed on 36 patients using a Nd:YLF-Laser at 527 nm (R:GEN ® , Lutronic, Goyang-Si, Republic of Korea). A total of 994 titration spots were examined using up to three years' multimodal imaging. Leakage in fluorescein angiography (FA) was observed after SRT in 523 lesions and resolved after one month. SRT lesions were not visible clinically, but appeared as brightly reflective areas in infrared and multicolor images. Normal morphology was observed in optical coherence tomography (OCT) immediately after SRT. After one month, thickening of the RPE and interdigitation zone changes were seen and disappeared after 539 ± 308 days. No RPE atrophies occurred during the observation period. Decreased fundus autofluorescence (FAF) was mostly observed directly after SRT followed by increased FAF at one month, which faded over time. A significant decrease in the number of visible lesions in the FA and FAF was observed within the three-year follow-up. OCT findings are consistent with animal studies showing SRT-related defect closure by hypertrophy and migration of neighboring cells without RPE atrophy or photoreceptor damage. This suggests that SRT is a safe treatment option for macular diseases and does not lead to retinal atrophy.

A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified-one tissue-nonspecific (TNAP) and three tissue-specific-named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. For instance, changes in the level of IAP activity can affect gut mucosa tolerance to microbial invasion due to the ability of IAP to detoxify bacterial endotoxins, alter the absorption of fatty acids and affect ectopurinergic regulation of duodenal bicarbonate secretion. To identify isozyme selective modulators of the human and mouse IAPs, we developed a series of murine duodenal IAP (Akp3-encoded dIAP isozyme), human IAP (hIAP), PLAP, and TNAP assays. High throughput screening and subsequent SAR efforts generated a potent inhibitor of dIAP, ML260, with specificity for the Akp3-, compared to the Akp5- and Akp6-encoded mouse isozymes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.

The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

With the advancement of high-throughput biomolecular screening techniques to the lead optimization stage, there is a critical need to quality control (QC) dose-response curves generated by robotic liquid handlers to ensure accurate affinity determinations. One challenge in evaluating the performance of liquid handlers is identifying and validating a robust method for testing dispense volumes across different instruments. Although traditional automated liquid handlers are still considered the standard platform in many laboratories, nanoliter dispensers are becoming more common and pose new challenges for routine quality control procedures. For example, standard gravimetric measurements are unreliable for testing the accuracy of nanoliter liquid dispenses. However, nanoliter dispensing technology allows for the conservation of compound, reduces compound carryover from well to well through discrete dispenses, and eliminates the need for intermediate compound dilution steps to achieve a low final DMSO assay concentration. Moreover, an intermediate dilution step in aqueous solution might result in compound precipitation at high concentrations. This study compared representative automation procedures done on a variety of liquid dispensers, including manual, traditional, and nanodispense volumes. The data confirmed the importance of establishing robust QC procedures for dose-response generation in addition to accuracy and precision determinations for each instrument, and they validated the use of nanoliter pipettors for dose-response testing. The results of this study also support the requirement for thorough mixing during serial compound dilutions prepared for high-throughput lead optimization strategies using traditional liquid handlers.

In analyzing Filipino migration to the United States since 1965, the authors identify two distinct chains of immigrants. One derives from the Filipinos who entered the country prior to 1965; the other comes from the flow of highly trained professionals who immigrated during the late 1960s and early 1970s. "To establish the historical basis for the two patterns of immigration that unfolded in the post-1965 period, the article begins with a brief examination of Filipino immigration to the United States. An analysis of the modes of entry used in both chains follows this overview. The study concludes with a discussion of the degree of convergence in these two chains and the consequences of each for contemporary Filipino-American community development." Data are from published U.S. census material and from Immigration and Naturalization Service reports and tapes dating from 1972 to 1985., (excerpt)

The pneumococci hitherto known as Group IV have been separated into ten types which have been designated by Roman numerals from IV to XIII. These have been correlated as far as possible with the types described by others. The prevalence and mortality of cases due to each type have been estimated in the limited number of cases studied. Laboratory tests indicated that therapeutic antiserums for Types I, II and III have very little protective power against the recently separated types. Monovalent antiserums of high agglutinative and protective power were prepared in rabbits for each type. Several monovalent antiserums each specific for a type, which are suitable for agglutination and experimental therapeutic use, have been obtained by immunizing horses. An antiserum prepared for one type had very little cross-protective power against other types.

The unclassified strains known as Group IV have been separated into twenty-nine types which are designated by the Roman numerals IV and XXXII. Only a small percentage of the pneumococcus strains isolated in New York City for this study were left unclassified. The majority of the types gave very slight cross-reactions, the exceptions being Types II and V, III and VIII, VII and XVIII and XV and XXX. In the series of cases studied, Types IV, V, VII and VIII were found more prevalent in the lobar pneumonia of adults and Types V, VI a and XIV in children. The majority of the types were also found in normal individuals and in persons having respiratory infections other than pneumonia. Types VI a and XIX were most prevalent in the limited number of strains studied by us. Fourteen of the types were found in pneumococcus meningitis; Type XVIII was found most often. Antisera suitable for clinical trial have been prepared for fourteen types. From the majority of the horses inoculated for more than a year, antisera having 500 to 1000 units per cc. were obtained. Antisera of lower potency were concentrated and preparations obtained equal to or stronger than high grade unconcentrated serum. Potent bivalent antisera have been prepared for types which were found to give marked cross-agglutination reactions. The results with each type as to prevalence, severity of cases, presence in normal individuals, and in spinal meningitis, potency of antisera produced for therapeutic trial and virulence of strains for mice have been considered under the different type headings.