Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Effect of adding Schroth physiotherapeutic scoliosis specific exercises to standard care in adolescents with idiopathic scoliosis on posture assessed using surface topography: A secondary analysis of a Randomized Controlled Trial (RCT).

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural asymmetry of the spine and trunk affecting 2-4% of adolescents. Standard treatment is observation, bracing, and surgery for small, moderate, and large curves, respectively. Schroth exercises aim to correct posture and reduce curve progression. PURPOSE: This study aimed to determine the effect of Schroth exercises added to the standard care compared to standard care alone on torso asymmetry in AIS. METHODS: In a randomized controlled trial (NCT01610908), 124 participants with AIS (age: 10-18, Cobb: 10°-45°, Risser: ≤3) were randomly assigned to the control (Standard care only) or Schroth (Standard care + Schroth treatment) group. Schroth treatment consisted of 1-hour weekly supervised sessions and 30-45 minutes of daily home exercises for six months. The control group received Schroth exercises in the last six months of the 1-year monitoring period. Markerless 3D surface topography assessed torso asymmetry measured by maximum deviation (MaxDev) and root mean square (RMS). Intention to treat linear mixed effects model analysis was compared to the per protocol analysis. RESULTS: In the intention to treat analysis, the Schroth group (n = 63) had significantly larger decreased RMS (-1.2 mm, 95%CI [-1.5,-0.9]mm, p = 0.012) and MaxDev (-1.9mm, 95%CI [-2.4,-1.5]mm, p = 0.025) measurements compared to controls (n = 57) after six months of intervention. In the per protocol analysis (Schroth n = 39, control n = 36), the Schroth group also had a significantly larger decrease compared to the control in both the RMS (-1.0mm, 95%CI [-1.9, -0.2]mm, p = 0.013) and MaxDev measurements (-2.0mm, 95%CI [-3.3,-0.5]mm, p = 0.037). For the control group, both the intention to treat and per protocol analysis showed no difference in RMS and MaxDev in the last six months of Schroth intervention (p>0.5). CONCLUSION: Schroth Exercise treatment added to standard care (observation or bracing) reduced asymmetry measurements in AIS. As expected, a greater effect was observed for participants who followed the prescribed exercise treatment per protocol.

Cytotoxic metabolites from Sinularia levi supported by network pharmacology.

The in-vitro anti-proliferative evaluation of Sinularia levi total extract against three cell lines revealed its potent effect against Caco-2 cell line with IC50 3.3 µg/mL, followed by MCF-7 and HepG-2 with IC50 6.4 µg/mL and 8.5 µg/mL, respectively, in comparison to doxorubicin. Metabolic profiling of S. levi total extract using liquid chromatography coupled with high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) revealed the presence of phytoconstituents clusters consisting mainly of steroids and terpenoids (1-20), together with five metabolites 21-25, which were additionally isolated and identified through the phytochemical investigation of S. levi total extract through various chromatographic and spectroscopic techniques. The isolated metabolites included one sesquiterpene, two steroids and two diterpenes, among which compounds prostantherol (21) and 12-hydroperoxylsarcoph-10-ene (25) were reported for the first time in Sinularia genus. The cytotoxic potential evaluation of the isolated compounds revealed variable cytotoxic effects against the three tested cell lines. Compound 25 was the most potent with IC50 value of 2.13 ± 0.09, 3.54 ± 0.07 and 5.67 ± 0.08 µg/mL against HepG-2, MCF-7 and Caco-2, respectively, followed by gorgosterol (23) and sarcophine (24). Additionally, network analysis showed that cyclin-dependent kinase 1 (CDK1) was encountered in the mechanism of action of the three cancer types. Molecular docking analysis revealed that CDK1 inhibition could possibly be the reason for the cytotoxic potential.

Niosomes as promising approach for enhancing the cytotoxicity of Hemimycale sp. total crude extract supported with in-silico studies.

The crude extract of Hemimycale sp. marine sponge was evaluated as a cytotoxic drug against different cell lines; whereas it exhibited promising selective activity toward the breast cancer cell line only with IC50 value 199.6 ± 0.00512 µg/ml. Moreover, its cytotoxic activity against the breast cancer cell line was reevaluated upon forming total extract-loaded niosomes. This revealed an IC50 value of 44.35 ± 0.011128 µg/ml, indicating the potential contribution of niosomes in boosting cell penetration and activity as a result. Owing to highlight the bioactive constituents responsible for the cytotoxic activity, metabolomics profiling of Hemimycale sp. was performed using liquid chromatography coupled with high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) revealing tentative identification of phytoconstituents clusters like as, diterpenes, sesterterpenes and sterols. Additionally, the cytotoxic activity of the crude extract was explained on the molecular level, whereas the dereplicated compounds were evaluated in silico against the Epidermal Growth Factor Receptor tyrosine kinase (EGFR). The sesterterpenoid derivatives phorbaketal A acetate (12) and secoepoxy ansellone A (13) together with mycalol-522 (17) showed the best binding energy.

A novel gelatinized barium sulfate injection method for assessment of bronchoalveolar lavage parameters.

INTRODUCTION: Bronchoalveolar lavage (BAL) is frequently used in pulmonary medicine though it requires further optimization. Practical obstacles such as patient safety and procedural limitation have to date precluded large, controlled trials aimed at standardization of BAL procedure. Indeed, BAL guidelines are based on observational data. Innovative research methods are necessary to advance the clinical practice of BAL. METHODS: In our study, we evaluated the effect of injecting a gelatinized barium solution into different lobes and segments of cadaveric lungs. As the technique requires an irreversible injection into lung airspaces, it is not suitable for in vivo purposes. We measured the volume returned from BAL as well as the distribution of BAL injection via dissection. Segmental anatomic orientation was compared to a radiologist's impression of plain film radiographs taken of injected lungs. RESULTS: Mean injected volume distributions were greatest in the upper lobes and lowest in the lower lobes; mean ratios of injected volume distribution to lung lobe volume also followed this trend. Cannulated bronchi orders favored lower branches in the upper lobe and higher branches in the lower lobes. Segmental anatomy varied by the lung lobe injected and was most varied in the lower lobes. CONCLUSION: This novel gelatinized-barium injection technique provides a minimally complex method to yield clinically meaningful feedback on the performance of BAL. The technique is also adaptable to study of procedural parameters in the context of variable lung anatomies and pathologies.

Paralemnalia thyrsoides-associated fungi: phylogenetic diversity, cytotoxic potential, metabolomic profiling and docking analysis.

BACKGROUND: Cancer continues to be one of the biggest causes of death that affects human health. Chemical resistance is still a problem in conventional cancer treatments. Fortunately, numerous natural compounds originating from different microbes, including fungi, possess cytotoxic characteristics that are now well known. This study aims to investigate the anticancer prospects of five fungal strains that were cultivated and isolated from the Red Sea soft coral Paralemnalia thyrsoides. The in vitro cytotoxic potential of the ethyl acetate extracts of the different five isolates were evaluated using MTS assay against four cancer cell lines; A549, CT-26, MDA-MB-231, and U87. Metabolomics profiling of the different extracts using LC-HR-ESI-MS, besides molecular docking studies for the dereplicated compounds were performed to unveil the chemical profile and the cytotoxic mechanism of the soft coral associated fungi. RESULTS: The five isolated fungal strains were identified as Penicillium griseofulvum (RD1), Cladosporium sphaerospermum (RD2), Cladosporium liminiforme (RD3), Penicillium chrysogenum (RD4), and Epicoccum nigrum (RD5). The in vitro study showed that the ethyl acetate extract of RD4 exhibited the strongest cytotoxic potency against three cancer cell lines A549, CT-26 and MDA-MB-231 with IC50 values of 1.45 ± 8.54, 1.58 ± 6.55 and 1.39 ± 2.0 µg/mL, respectively, also, RD3 revealed selective cytotoxic potency against A549 with IC50 value of 6.99 ± 3.47 µg/mL. Docking study of 32 compounds dereplicated from the metabolomics profiling demonstrated a promising binding conformation with EGFR tyrosine kinase that resembled its co-crystallized ligand albeit with better binding energy score. CONCLUSION: Our results highlight the importance of soft coral-associated fungi as a promising source for anticancer metabolites for future drug discovery.

Tail-approach based design, synthesis, and cytotoxic evaluation of novel disubstituted and trisubstituted 1,3-thiazole benzenesulfonamide derivatives with suggested carbonic anhydrase IX inhibition mechanism.

A novel series of 2,4,5- and 2,3,4-trisubstituted thiazole hybrids with 1,3,4-thiadiazolylbenzenesulfonamide was designed following the tail approach as possible hCAIX inhibitors. The key intermediate 1 was condensed with thiosemicarbazide 2a to give 1,3,4-thiadiazolylthiosemicarbazone 3, which upon hetero-cyclization with substituted α-haloketones and esters afforded 2,4,5-trisubstituted thiazole-1,3,4-thiadiazole conjugates 4-8. Furthermore, the trisubstituted thiazole-1,3,4-thiadiazole hybrids 12a-d were synthesized via the regioselective cyclization of 4-substituted-1,3,4-thiadiazolylthiosemicarbazones with phenacyl bromide. The cyclized 2,4-disubstituted thiazole 4 enhanced cytotoxicity by nine, four and two times against HepG-2, Caco2, and MCF-7, respectively. Moreover, the simple methyl substitution on the thiosemicarbazone terminus 9a improved the parent derivative 3 cytotoxicity by nine, fourteen, and six times against HepG-2, Caco2, and MCF-7, respectively. This astonishing cytotoxicity was elaborated with hCAIX molecular docking simulation of 4, 9a, and 12d demonstrating binding to zinc and its catalytic His94. Furthermore, molecular dynamic simulation 9a revealed stable hydrogen bonding with hCAIX with interaction energy of -61.07 kcal mol-1 and ΔGbinding MM-PBSA of -9.6 kcal mol-1.

Rat-Bite Fever in a 34-Year-Old Female.

Rat-bite fever (RBF) is a rare systemic infectious disease caused by Streptobacillus moniliformis, Spirillum minus, or Streptobacillus notomytis. As the name implies, the disease is typically transmitted by a rat bite. RBF usually presents as a combination of fever, arthritis, and rash. Definitive diagnosis of RBF may prove difficult, as the responsible bacteria are not easily identified with standard testing. We describe a case of RBF in a 34-year-old female who presented with fever, chills, polyarthralgia, and skin rash following a rat bite. Initial vital signs were remarkable for fever and tachycardia. Physical examination revealed an erythematous vesicular and papular rash involving her extremities, buttocks, and oral mucosa. Blood cultures were negative. A skin biopsy revealed leukocytoclastic vasculitis and was negative for Gram stain. Further analysis using specialized immunohistochemistry and polymerase chain reaction (PCR) identified S. moniliformis. A diagnosis of RBF was made, and the patient was successfully treated with a two-week course of doxycycline.

Cytokeratin-20 negative nodal Merkel cell carcinoma with regressed primary: a potential pitfall in interpretation of nodal metastasis.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma that affects sun-damaged skin. Histologically, the tumor consists of round cells with fine chromatin positive for cytokeratin 20 in ~90% of cases. Rare cases of MCC can regress spontaneously and present as nodal metastasis. Nodal MCC of unknown primary can cause a potential pitfall as they can be misinterpreted as other neuroendocrine carcinomas such as small cell carcinoma. We report a case of nodal MCC with an atypical immunohistochemistry pattern presented as bilateral axillary lymphadenopathy in a 90-year-old man with a remote history of a skin lesion that healed spontaneously leaving a scar.

Proteogenomic Approaches for the Identification of NF1/Neurofibromin-depleted Estrogen Receptor-positive Breast Cancers for Targeted Treatment.

NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader, together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ patient-derived xenograft (PDX) models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pulldown. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An IHC assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER+ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis. Significance: A major challenge for targeting the consequence of tumor suppressor disruption is the accurate assessment of protein functional inactivation. NF1 can repress both RAS and ER signaling, and a ComboMATCH trial is underway to treat the patients with binimetinib and fulvestrant. Herein we report a MS-verified NF1 IHC assay that can determine a threshold for NF1 loss to predict treatment response. These approaches may be used to identify and expand the eligible patient population.

Extranodal Natural Killer/T-cell Lymphoma Isolated to the Leg: A Case Report.

Extranodal natural killer/T-cell lymphoma (ENKTL) is a subtype of non-Hodgkin's lymphoma, and it is exceedingly rare in North America. The "extranasal" subtype of ENKTL frequently involves the skin and typically has an aggressive course with no current standard of treatment available. In this report, we present a case of cutaneous ENKTL in an otherwise healthy middle-aged male.

Primary vulvar extragastrointestinal stromal tumor in a 77-year-old woman.

Extragastrointestinal stromal tumors (EGISTs) carry the same morphological, immunohistochemical and molecular features as gastrointestinal stromal tumors (GISTs) and involve extragastrointestinal tract soft tissue. The majority of reported EGIST cases arise from intraabdominal, retroperitoneal, or pelvic soft tissue. A significant subset of such tumors originates from the gastrointestinal muscle layer, grows in an exophytic manner, then loses attachment to the gastrointestinal tract. Consequently, true EGISTs are exceedingly rare. Herein, we are reporting a case of a vulvar EGIST. A 77-year-old woman presented with a painless subcutaneous nodule on the right perineum. An excisional biopsy showed a fairly circumscribed bland spindle cell lesion in the dermis. The tumor cells were positive for CD117 and ANO1/DOG-1 and negative for smooth muscle myosin, smooth muscle actin, STAT6, low- and high-molecular-weight cytokeratins, SOX10, MART-1, CD10, S-100 protein, and estrogen and progesterone receptors. A diagnosis of EGIST was made and complete excision was recommended. Superficial/subcutaneous EGISTs are extremely rare, and it is important for dermatopathologists to be aware of this entity as it can be misdiagnosed as more common spindle cell neoplasms, both benign and malignant, including but not limited to smooth muscle neoplasms (leiomyoma/leiomyosarcoma), spindle cell melanoma, and sarcomatoid squamous cell carcinoma.

Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study.

Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b.

Acceptance of Acute Kidney Injury Alert by Providers in Cardiac Surgery Intensive Care Unit.

BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Its management relies on early diagnosis, and therefore, electronic alerts have been used to alert clinicians for development of AKI. Electronic alerts are, however, associated with high rates of alert fatigue. OBJECTIVES: We designed this study to assess the acceptance of user-centered electronic AKI alert by clinicians. METHODS: We developed a user-centered electronic AKI alert that alerted clinicians of development of AKI in a persistent yet noninterruptive fashion. As the goal of the alert was to alert toward new or worsening AKI, it disappeared 48 hours after being activated. We assessed the acceptance of the alert using surveys at 6 and 12 months after the alert went live. RESULTS: At 6 months after their implementation, 38.9% providers reported that they would not have recognized AKI as early as they did without this alert. This number increased to 66.7% by 12 months of survey. Most providers also shared that they re-dosed or discontinued medications earlier, provided earlier management of volume status, avoided intravenous contrast use, and evaluated patients by using point-of-care ultrasounds more due to the alert. Overall, 83.3% respondents reported satisfaction with the electronic AKI alerts at 6 months and 94.4% at 12 months. CONCLUSION: This study showed high rates of acceptance of a user-centered electronic AKI alert over time by clinicians taking care of patients with AKI.

Secondary syphilis presenting as leukocytoclastic vasculitis in a 61-year-old man.

Cutaneous lesions of secondary syphilis are highly infectious and can mimic many skin disorders, making the diagnosis more difficult. They typically present as generalized, nonpruritic erythematous-to-copper-colored macules and papules, characteristically involving palms and soles. In 80% of patients the rash develops insidiously. However, rare forms of secondary syphilis present as rapidly progressive papulopustular lesions. These forms of syphilis are usually associated with human immunodeficiency virus infection and immunosuppression. We report a case of secondary syphilis presenting with an acute, rapidly progressive purpuric eruption mimicking leukocytoclastic vasculitis. A 61-year-old man presented with a 6-day history of nonpruritic rash on his chest and lower extremities associated with fatigue, sore throat, and night sweats. Examination revealed purpuric papules, extending from the dorsal feet to the hips; mucosal surfaces were not involved. A diagnosis of cutaneous small-vessel vasculitis was favored with possible triggers of IgA vasculitis. Initial work-up showed acute kidney injury and microscopic hematuria. Renal biopsy showed IgA nephropathy with mesangioproliferative glomerulonephritis. The patient's rash progressed to cover almost his entire body sparing palms and soles. Skin biopsy showed heavy perivascular lymphoplasmacytic infiltrate, capillary endothelial cell swelling, and sparse perivascular neutrophilic nuclear dust. Spirochetal stain highlighted scattered epidermal and dermal organisms.

The Potential of Corchorus olitorius Seeds Buccal Films for Treatment of Recurrent Minor Aphthous Ulcerations in Human Volunteers.

Aphthous ulcers are very common disorders among different age groups and are very noxious and painful. The incidence of aphthous ulcer recurrence is very high and it may even last for a maximum of 6 days and usually, patients cannot stand its pain. This study aims to prepare a buccoadhesive fast dissolving film containing Corchorus olitorius seed extract to treat recurrent minor aphthous ulceration (RMAU) in addition to clinical experiments on human volunteers. An excision wound model was used to assess the in vivo wound healing potential of Corchorus olitorius L. seed extract, with a focus on wound healing molecular targets such as TGF-, TNF-, and IL-1. In addition, metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds was explored. Moreover, molecular docking experiments were performed to elucidate the binding confirmation of the isolated compounds with three molecular targets (TNF-α, IL-1ß, and GSK3). Additionally, the in vitro antioxidant potential of C. olitorius seed extract using both H2O2 and superoxide radical scavenging activity was examined. Clinical experiments on human volunteers revealed the efficiency of the prepared C. olitorius seeds buccal fast dissolving film (CoBFDF) in relieving pain and wound healing of RMAU. Moreover, the wound healing results revealed that C. olitorius seed extract enhanced wound closure rates (p ≤ 0.001), elevated TGF-ß levels and significantly downregulated TNF-α and IL-1ß in comparison to the Mebo-treated group. The phenotypical results were supported by biochemical and histopathological findings, while metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds yielded a total of 21 compounds belonging to diverse chemical classes. Finally, this study highlights the potential of C. olitorius seed extract in wound repair uncovering the most probable mechanisms of action using in silico analysis.

Association between the Use of Quantitative Sensory Testing and Conditioned Pain Modulation and the Prescription of Medication and Interventional Procedures in Children with Chronic Pain Conditions.

The evidence supporting the use of pharmacological treatments in pediatric chronic pain is limited. Quantitative sensory testing (QST) and conditioned pain modulation evaluation (CPM) provide information on pain phenotype, which may help clinicians to tailor the treatment. This retrospective study aimed to evaluate the association between the use of QST/CPM phenotyping on the selection of the treatment for children with chronic pain conditions. We retrospectively analyzed the medical records of 208 female patients (mean age 15 ± 2 years) enrolled in an outpatient interdisciplinary pediatric complex pain center. Pain phenotype information (QST/CPM) of 106 patients was available to the prescribing physician. The records of 102 age- and sex-matched patients without QST/CPM were used as controls. The primary endpoint was the proportion of medications and interventions prescribed. The secondary endpoint was the duration of treatment. The QST/CPM group received less opioids (7% vs. 28%, respectively, p < 0.001), less anticonvulsants (6% vs. 25%, p < 0.001), and less interventional treatments (29% vs. 44%, p = 0.03) than controls. Patients with an optimal CPM result tended to be prescribed fewer antidepressants (2% vs. 18%, p = 0.01), and patients with signs of allodynia and/or temporal summation tended to be prescribed fewer NSAIDs (57% vs. 78%, p = 0.04). There was no difference in the duration of the treatments between the groups. QST/CPM testing appears to provide more targeted therapeutic options resulting in the overall drop in polypharmacy and reduced use of interventional treatments while remaining at least as effective as the standard of care.

Antitumor and Protective Activity of TVLE against CdCl2-Induced Renal Damage in Rats.

<b>Background and Objective:</b> Cadmium is a heavy metal that has a wide range of applications in human existence. Cadmium may bind to the protein metallothionein and decrease kidney function once it enters the body. The purpose of this study was to investigate the renal protective activity of TVLE against CdCl₂-induced renal toxicity in rats. <b>Materials and Methods:</b> TVLE was prepared and characterized using instrumental analysis and spectral data. Furthermore, the IC₅₀ of TVLE against the Vero renal carcinoma cell line was calculated. Adult albino rats were used to assess the renal protective activity of TVLE (150 and 300 mg kg¹ b.wt.) in CdCl₂-treated rats. <b>Results:</b> IC₅₀of TVLE against Vero cell line equals 148.25 µg mL¹. The daily oral administration of TVLE at concentrations of 150 and 300 mg kg¹ b.wt. for 21 days to CdCl₂-treated rates resulted in a significant improvement in tumour volume and tumour weight, urea, creatinine, uric acid, TNF-α, NOx, TBARs, GSH, CAT, SOD, GPx and VEGF-C gene expression in CdCl₂-treated rats. Furthermore, TVLE almost normalized these effects in renal histoarchitecture. <b>Conclusion:</b> The biochemical, histological and MRI examinations of the current study suggested that TVLE have renal protective activity against CdCl₂-induced renal toxicity in rats.

Synthesis, molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity.

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (KI = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing KI of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.

TAG (Tube and Graft) Sandwich Technique: A Novel Single-Stage Scleral Reinforcement and Aqueous Drainage Tube Implantation.

PURPOSE: Refractory glaucoma patients continue to require surgical intervention in the form of trabeculectomy surgery or glaucoma drainage device (GDD). Those patients that require a GDD but have thin sclera or scleromalacia present a challenge. METHODS: In this article, we present a novel "TAG sandwich" single surgical procedure in which thinned sclera is reinforced with a pericardial patch graft ("bottom layer of the sandwich") allowing safe implantation of the GDD ("the tube sandwich filling") and then placing another patch graft on top of the tube part of the GDD ("top layer of the sandwich"). The surgery was performed on an open-angle glaucoma patient with a generalized thin sclera and uncontrolled intraocular pressure despite maximal topical medication and oral acetazolamide. RESULTS: Reinforcing a compromised sclera with a pericardium patch graft allowed the safe implantation of a glaucoma drainage device. The patient's intraocular pressure was safely controlled at 7 mmHg almost 1-year postsurgery without intraocular pressure-lowering drops. CONCLUSIONS: This scleral strengthening procedure can be considered by readers in other ocular surgeries where there is a risk of scleral perforation, as well as part of a combined surgery where refractory glaucoma patients with thin sclera require scleral reinforcement to allow for safer implantation of a glaucoma drainage device.