Phytochemical profiling, antioxidant potential and cytotoxic activity of Sargassum prismaticum extracts: implications for therapeutic applications.

Seaweeds are sources of bioactive compounds with medicinal properties, which make them attractive candidates for natural therapeutic agents. Marine brown algae are known to possess anti-inflammatory, hepatoprotective, anticancer properties, etc. Present study was carried out to identify the phytochemical constituents, antioxidant and cytotoxic activities of Sargassum prismaticum in two different solvents viz., chloroform and methanol. Chloroform was found to be the superior solvent for phenol and flavonoid extraction. Antioxidant activity was determined using DPPH and ABTS assays; however, the methanolic extract demonstrated better antioxidant potential. The highest cell cytotoxicity with an IC50 value of 7.6 ± 0.02 µg/mL was observed in methanolic extract, while the chloroform extract had an IC50 value of 9.6 ± 0.03 µg/mL against U937 cell line. These finding suggest that Sargassum prismaticum possesses potent antioxidant and cytotoxic properties, making it a potential candidate for further study as a novel antioxidant drug source.

Biomechanical analysis and comparison between 'Zeta' miniplate design and conventional miniplate system for fixation of fracture segments in transition zone of parasymphysis body region of mandible - an in vitro study.

The parasymphysis area of the mandible is highly dynamic because it is subjected to both occlusal and muscular forces. As a result, the fractures in this transition zone have a special pattern, posing a challenge for surgeons whether to use one miniplate versus two miniplates, as per Champy's recommendations. The commonest complication resulting to treat this area is mental nerve paraesthesia due to the dissection and stretching of the nerve. Hence, an in vitro research study of a newly designed 'Zeta' miniplate is performed, to evaluate the biomechanical behaviour using finite element (FE) analysis and biomechanical analysis along with a comparison study with the conventional miniplate configurations. The results showed that the Zeta miniplate produces the lowest stresses 17.511 MPa and the least total structural deformation of 0.0011 mm after applying the maximum occlusal bite force. On application of torsional load, total structural deformation was 0.0004 mm and von Mises (VM) stress value was 0.24 MPa which was lowest when compared with the two miniplate system. Hence, the newly developed Zeta miniplate is superior in terms of stability. Another benefit of its design is that it helps in preventing mental nerve paraesthesia and tooth root damage while fixing and stabilising the fractured bony segments.

An Unusual Case of Symptomatic Isolated Lingual Cysticercosis: Clinical Suspicion Helped Prevent Disseminated Disease.

Intraorally, cysticercosis is regarded as uncommon and a diagnostic challenge. Here, we report a diagnostic conundrum of an unusual case of innocuous appearing lesion on the tongue presenting as moderately tender swelling finally diagnosed as lingual cysticercosis, based on USG (Ultrasound), CT (Computed Tomography) findings and characteristic histopathologic features.

Unified deep learning models for enhanced lung cancer prediction with ResNet-50-101 and EfficientNet-B3 using DICOM images.

Significant advancements in machine learning algorithms have the potential to aid in the early detection and prevention of cancer, a devastating disease. However, traditional research methods face obstacles, and the amount of cancer-related information is rapidly expanding. The authors have developed a helpful support system using three distinct deep-learning models, ResNet-50, EfficientNet-B3, and ResNet-101, along with transfer learning, to predict lung cancer, thereby contributing to health and reducing the mortality rate associated with this condition. This offer aims to address the issue effectively. Using a dataset of 1,000 DICOM lung cancer images from the LIDC-IDRI repository, each image is classified into four different categories. Although deep learning is still making progress in its ability to analyze and understand cancer data, this research marks a significant step forward in the fight against cancer, promoting better health outcomes and potentially lowering the mortality rate. The Fusion Model, like all other models, achieved 100% precision in classifying Squamous Cells. The Fusion Model and ResNet-50 achieved a precision of 90%, closely followed by EfficientNet-B3 and ResNet-101 with slightly lower precision. To prevent overfitting and improve data collection and planning, the authors implemented a data extension strategy. The relationship between acquiring knowledge and reaching specific scores was also connected to advancing and addressing the issue of imprecise accuracy, ultimately contributing to advancements in health and a reduction in the mortality rate associated with lung cancer.

Clear cell oral squamous cell carcinoma as a diagnostic conundrum: report of 2 rare cases.

The occurrence of clear cell histologic sub-type of oral squamous cell carcinoma in the oral cavity is a distinct and exceedingly rare entity exhibiting aggressive behavior. To date, only 10 cases have been published in the literature. We describe 2 extremely rare cases, both presenting with swelling and ulcerated nodule-like proliferative growth in the mandible. Microscopically, sheets and lobules of neoplastic squamous epithelial cells showing clear cell differentiation were appreciated in both patients. Periodic acid-Schiff and mucicarmine revealed negative staining. Immunohistochemical (IHC) analysis for antibody for renal cell tumor marker CD 10 was immune-negative. The malignant clear cells in both cases showed intense positive reactions with IHC markers pan-cytokeratin and epithelial membrane antigen, confirming the diagnosis as a clear cell variant of oral squamous cell carcinoma (CCOSCC). The first patient was unwilling for treatment and eventually died within 2 months of the diagnosis. In the second patient, right hemi-mandibulectomy with level 1A and 1B lymph nodes was performed. Adjuvant chemotherapy with low-dose methotrexate was initiated. Follow-up after 2 months of surgery was uneventful. Current rare reports emphasize the significance of prompt and extensive diagnostic work-up of clear cell neoplasms, as the CCOSCC may be fatal.

i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists.

The ability to leverage antibodies to agonize disease relevant biological pathways has tremendous potential for clinical investigation. Yet while antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biology of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Here, we describe an engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. iAb engineering provides a tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.

A new onset drug induced diabetes mellitus presenting with diabetic ketoacidosis in a child undergoing treatment for B cell acute lymphoblastic leukemia. A case report and review of literature.

OBJECTIVES: Hyperglycemia is a known side effect of anticancer chemotherapeutic drugs. This entity known as drug-induced diabetes mellitus usually does not present with the development of diabetic ketoacidosis (DKA). We hereby report a case of drug induced diabetes mellitus in a child with acute leukemia presenting with DKA. CASE PRESENTATION: We report a case of a teenage boy diagnosed with B cell acute lymphoblastic leukemia and was started on induction phase chemotherapy as per the Indian Collaborative Childhood Leukemia group (ICICLe) acute lymphoblastic leukemia-14 protocol. On day 12 of the induction phase, he developed hyperglycemia and presented to us with severe diabetic ketoacidosis (DKA). Serum anti glutamic acid decarboxylase 65 antibody levels were negative with low serum C peptide levels. Initially, the possibility of drug-induced acute pancreatitis was kept which was ruled out. Keeping the possibility of drug-induced hyperglycemia, the child was started on subcutaneous regular insulin which was titrated as per sugar records. Continuation of remaining chemotherapy was done by PEGylated L-asparaginase with titration of insulin as per home-based sugar records. Insulin requirement increased from 0.3 unit/kg/day to a maximum of 1 unit/kg/day during consolidation phase 1 with PEGylated L-asparaginase suggesting drug-induced hyperglycemia but subsequently insulin requirement decreased and insulin was stopped. CONCLUSIONS: Drug induced diabetes mellitus can present as DKA during induction phase of acute lymphoblastic leukemia (ALL) chemotherapy. A high index of suspicion and close monitoring are required. The insulin requirements in these patients can be very fluctuant and may become nil during the course of treatment.

Nanoemulsion potentiates the anti-cancer activity of Myricetin by effective inhibition of PI3K/AKT/mTOR pathway in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is a heterogeneous tumor with a poor prognosis and high metastatic potential, resulting in poor clinical outcomes, necessitating investigation to devise effective therapeutic strategies. Multiple studies have substantiated the anti-cancer properties of the naturally occurring flavonoid "Myricetin" in various malignancies. However, the therapeutic application of Myricetin is impeded by its poor water solubility and low oral bioavailability. To overcome this limitation, we aimed to develop nanoemulsion of Myricetin (Myr-NE) and evaluate its advantage over Myricetin alone in TNBC cells. The nanoemulsion was formulated using Capryol 90 (oil), Tween 20 (surfactant), and Transcutol HP (co-surfactant). The optimized nano-formulation underwent an evaluation to determine its size, zeta potential, morphology, stability, drug encapsulation efficiency, and in vitro release properties. The anti-cancer activity of Myr-NE was further studied to examine its distinct impact on intracellular drug uptake, cell-viability, anti-tumor signaling, oxidative stress, clonogenicity, and cell death, compared with Myricetin alone in MDA-MB-231 (TNBC) cells. The in vitro drug release and intracellular drug uptake of Myricetin was significantly increased in Myr-NE formulation as compared to Myricetin alone. Moreover, Myr-NE exhibited significant inhibition of cell proliferation, clonogenicity, and increased apoptosis with ~ 2.5-fold lower IC50 as compared to Myricetin. Mechanistic investigation revealed that nanoemulsion augmented the anti-cancer efficacy of Myricetin, most likely by inhibiting the PI3K/AKT/mTOR pathway, eventually leading to enhanced cell death in TNBC cells. The study provides substantial experimental evidence to support the notion that the Myr-NE formulation has the potential to be an effective therapeutic drug for TNBC treatment.

Efficacy of anti-suppression therapy in improving binocular vision in children with small-angle Esotropia.

PURPOSE: To evaluate the efficacy of anti-suppression exercises in children with small-angle esotropia in achieving binocular vision. METHODS: A retrospective review of patients aged 3-8 years who underwent anti-suppression exercises for either monocular or alternate suppression between January 2016 and December 2021 was conducted. Patients with esotropia less than 15 prism diopters (PD) and visual acuity ≥ 6/12 were included. Patients with previous intra-ocular surgery or less than three-month follow-up were excluded. Success was defined as the development of binocular single vision (BSV) for distance, near, or both (measured clinically with either the 4 prism base out test or Worth four dot test) and maintained at two consecutive visits. Qualified success was defined as the presence of diplopia response for both distance and near. Additionally, improvement in near stereo acuity was measured using the Stereo Fly test. RESULTS: Eighteen patients with a mean age of 5.4 ± 1.38 years (range 3-8 years) at the time of initiation of exercises were included in the study. The male female ratio was 10:8. The mean best corrected visual acuity was 0.18 LogMAR unit(s) and the mean spherical equivalent was +3.8 ± 0.14 diopters (D). The etiology of the esotropia was fully accommodative refractive esotropia (8), microtropia (1), post-operative infantile esotropia (4), partially accommodative esotropia (1), and post-operative partially accommodative esotropia (4). Patients received either office-based, home-based, or both modes of treatment for an average duration of 4.8 months (range 3-8). After therapy, BSV was achieved for either distance or near in 66.6 % of patients (95 % CI = 40.03-93.31 %). Binocular single vision for both distance and near was seen in 50 % of children. Qualified success was observed in 38.46% of patients. Persistence of suppression was observed in one patient (5.5 %). Near stereopsis improved to 200 s of arc or more in 60% of the patients. The mean esotropia reduced from 5.7 ± 4.0 PD for distance and 6.2 ± 4.66 PD for near to 2.7 ± 2.4 PD and 3.38 ± 4.7 PD respectively, at the last follow-up (p-value 0.004 and 0.006). Failure of therapy was noticed after six months of follow-up in the child with infantile esotropia. CONCLUSION: Anti-suppression exercises may be beneficial to improve binocular vision functions in children with small-angle esotropias of variable etiologies. Recurrence of suppression after cessation of therapy is possible, warranting regular follow up.

Circulatory Maternal Endothelin 1 and Matrix Metalloproteinase-9 Gene Expression in PREECLAMPSIA: A Study in Western Uttar Pradesh, India.

Introduction: Preeclampsia (PE) is a multiorgan disease of pregnant women. The main pathophysiology of PE is a trophoblastic invasion into maternal circulation leading to alterations in circulatory levels of matrix metalloproteinases (MMPs), inflammatory markers, and endothelin 1(ET1) levels. Therefore, the present study has explored the role of MMP-9 and ET1 and their association in PE. The advantage of the study is to provide insight into the pathology of PE. These markers may help in the early diagnosis and prognosis of PE. Objective: To investigate MMP-9 gene expression, ET1 level in PE cases and their correlation with blood pressure (BP), gestational age, weight, and height. Methods: The study design was a case-control observational study, which included 70 subjects in each case (PE) and controls (normal pregnant women (NPW)). Whole blood (250 ul) was utilized for RNA extraction (Trizol method) and synthesized cDNA as per manufacturer protocol. MMP-9 gene expression was analyzed by real-time PCR. Serum was utilized for ET1 estimation by sandwich ELISA. Results: The ET1 levels and MMP-9 gene expression were significantly increased in preeclamptic women as compared to controls. There was no significant correlation between MMP-9 gene expression and serum ET1 levels. However, a significant moderate association between systolic BP and diastolic BP with ET1 levels and MMP9 gene expression was seen in both PE and NPW. Conclusion: A significantly increased circulatory concentration of ET1 and MMP-9 gene expression in PE might be used as an early diagnostic as well as a prognostic marker of PE.

A Comparative Analysis of Phytochemicals, Metal Ions, Volatile Metabolites in Heart Wood, Stem Bark and Leaves of Salix alba L. along with in Vitro Antioxidant, Antacid, Antimicrobial Activities for Sake of Environment Conservation by Substitution of Stem Bark With Leaf.

The genus of Salix is used in food, medicine and nutraceuticals, and standardized by using the single marker compound Salicin only. Stem bark is the official part used for the preparation of various drugs, nutraceuticals and food products, which may lead to overexploitation and damage of tree. There is need to search substitution of the stem bark with leaf of Salix alba L. (SA), which is yet not reported. Comparative phytochemicals viz. Salicin, Procyanidin B1 and Catechin were quantified in the various parts of SA viz. heart wood (SA-HW), stem bark (SA-SB) and leaves (SA-L) of Salix alba L.by using newly developed HPLC method. It was observed that SA-HW and SA-L contained far better amount of Salicin, Procyanidin B and Catechin as compared to SA-SB (SA-HW~SA-L≫SA-SB). Essential and toxic metal ions of all three parts were analysed using newly developed ICP-OES method, where SA-L were founded as a rich source of micronutrients and essential metal ions as compared to SA-SB and SA-HW. GC-MS analysis has shown the presence of fatty acids and volatile compounds. The observed TPC and TFC values for all three parts were ranged from 2.69 to 32.30 mg GAE/g of wt. and 37.57 to 220.76 mg QCE/g of wt. respectively. In DPPH assay the IC50 values of SA-SB, SA-HW, and SA-L were 1.09 (±0.02), 5.42 (±0.08), and 8.82 (±0.10) mg/mL, respectively. The order of antibacterial activities against E. coli, S. aureus, P. aeruginosa, and B. subtilis strains was SA-L>SA-HW>SA-SB with strong antibacterial activities against S. aureus, and B. subtilis strains. The antacid activities order was SA-L>SA-SB>SA-HW. The leaves of SA have shown significant source of nutrients, phytochemicals and medicinal properties than SA-HW and SA-SB. The leaves of SA may be considered as substitute of stem bark to save the environment or to avoid over exploitation, but after the complete pharmacological and toxicological studies.

A comparative analysis between intra articular injections of injectable platelet rich fibrin versus platelet rich plasma in the management of temporomandibular disorders: A randomized control trial.

Background: Platelet concentrate has become an increasingly popular alternative source of growth factors for several types of dental and surgical procedures. It improves healing and stimulates cell proliferation, matrix remodeling, and angiogenesis. The injectable platelet-rich fibrin (i-PRF) has various advantages over platelet-rich plasma (PRP). The aim of our study was to evaluate the efficacy of intra-articular injections of i-PRF versus PRP in the management of temporomandibular disorders (TDMs). Method: The prospective randomized study involved 14 patients (N = 28 joints) of internal derangement between the age groups of 20 to 50 years divided randomly into two groups with seven patients (N = 14 joints) in each group. For all the patients, arthrocentesis was carried out in the first sitting followed by intra-articular injections of PRP and i-PRF in group I and group II, respectively, at 1-month interval for 6 months. A single surgeon has performed the procedure. All patients were assessed clinically for pain, maximal mouth opening (MMO), lateral movement, protrusive movement, and joint sounds and radiographically for disc position and joint effusion (JE). Results: Pain reduction, MMO, lateral movement, protrusive movement, and joint sounds were significant in both groups with more significance in group II. Disc position had improved toward normal in both groups and showed significant changes in both groups at the 9-month follow-up with better results in group II. Conclusion: PRP and i-PRF injections are regarded as simple and safe methods with potential beneficial effects and are cost-effective. In this preliminary study, i-PRF has been found to be scoring better in terms of efficacy over PRP across all set parameters.

Pseudo-Lyre Sign.

To study the causes of the Pseudo- Lyre sign which is radiologically demonstrated in tumours other than the carotid body tumour. The study is based on an unusual case of neurofibroma of the cervical sympathetic chain presenting as a pulsatile mass in the carotid triangle in a 34 years female. Radiological investigation pointed to a diagnosis of a carotid body tumour because of typical splaying of the internal and external arteries causing the Lyre sign. At surgery, the tumour which was arising from the cervical sympathetic chain (CSC) was excised with minimum blood loss and histopathology confirmed it to be neurofibroma. This, we presume is the first ever report of a neurofibroma of the cervical sympathetic chain causing Lyre sign which we have referred to as Pseudo-Lyre sign. The various investigations which help in diagnosing the cause of Pseudo-Lyre sign have been discussed. All tumours causing Lyre sign on radio-imaging are not carotid body tumours. Other masses mostly neurogenic can demonstrate this sign and an attempt should be made preoperatively to confirm the diagnosis.

Anatomical Variations of the Optic Nerve in the Sphenoid Sinus: Do Ethnic Variations Matter?

There are several variations in the anatomical relations of the optic nerve with the sphenoid sinus. Proper understanding of these variations is clinically important to minimize injuries associated with surgical procedures that involve the sphenoid sinus. CT scans of paranasal sinuses obtained prior to any endoscopic surgery in the sphenoid sinus area is useful for designing operative strategies. Ethnic variations in sinonasal anatomy have been documented. The objective was to study the pattern of relationship between optic nerve and the sphenoid sinus using computerized tomographic imaging in a north Indian population, to compare our findings with previous studies in different ethnic groups and find out if ethnic variations in such a relationship matter. A prospective study was conducted on 300 patients who underwent computed tomography of the paranasal sinuses from Sept 2020 to June 2021. Relationship of optic nerves to the sphenoid sinuses was categorized according to DeLano classification. Pneumatization of the anterior clinoid process and bony dehiscence of optic nerve was also observed. Type 1 position of optic nerve was seen in 69.3%, Type 2 in 20.9%, Type 3 in 3% and Type 4 in 6.8% of sinuses. The pneumatization of anterior clinoid process (ACP) was observed in 10.5% and the bony dehiscence of optic nerve was noted in 6.5% sinuses. Bony dehiscence of optic canal had associated ACP pneumatization in 64.1% sinuses.The variability of the relation of optic nerve to the sphenoid sinus even in the persons of same ethnicity precludes a definite role of ethnicity in these variations. Other factors possibly contributing to such a relationship have been discussed.

Toxicity analysis of endocrine disrupting pesticides on non-target organisms: A critical analysis on toxicity mechanisms.

Endocrine disrupting compounds are the chemicals which mimics the natural endocrine hormones and bind to the receptors made for the hormones. Upon binding they activate the cascade of reaction which leads to permanent activating of the signalling cycle and ultimately leads to uncontrolled growth. Pesticides are one of the endocrine disrupting chemicals which cause cancer, congenital birth defects, and reproductive defects in non-target organisms. Non-target organisms are keen on exposing to these pesticides. Although several studies have reported about the pesticide toxicity. But a critical analysis of pesticide toxicity and its role as endocrine disruptor is lacking. Therefore, the presented review literature is an endeavour to understand the role of the pesticides as endocrine disruptors. In addition, it discusses about the endocrine disruption, neurological disruption, genotoxicity, and ROS induced pesticide toxicity. Moreover, biochemical mechanisms of pesticide toxicity on non-target organisms have been presented. An insight on the chlorpyrifos toxicity on non-target organisms along with species names have been presented.

Evaluation of the Use of Appetite Stimulants in Pediatric Patients with Cystic Fibrosis.

OBJECTIVE: Poor nutrition in patients with cystic fibrosis (CF) has been associated with lower lung function and increased morbidity and mortality. Conversely, better nutritional status has been associated with improved pulmonary function and fewer CF-associated complications. There is no consensus regarding appetite stimulant therapy in patients with CF (pwCF). The primary objective of this study was to determine if the use of appetite stimulants was associated with weight changes in pediatric pwCF in the ambulatory care setting. METHODS: This was a retrospective study that evaluated 62 pediatric pwCF who received cyproheptadine or mirtazapine for appetite stimulation for at least 6 consecutive months. Weight z scores were collected for each patient at baseline, 3, 6, and 12 months of therapy, if available. RESULTS: Increase in weight z score after 3 months of therapy was statistically significant based on both univariable and multivariable models when evaluating the entire cohort. The adjusted mean difference for change in weight z score was 0.33 ( P < 0.001) from baseline to month 3. There was a statistically significant improvement in pulmonary function after 3 and 6 months of therapy. CONCLUSIONS: Appetite stimulant therapy was associated with improvement in weight z score in the first 3 months of treatment. Appetite stimulant therapy was associated with improvement in pulmonary function in the first 3 months of therapy, which supports the relationship between weight gain and improved pulmonary function in pwCF. These findings suggest that appetite stimulants contribute to weight gain in pediatric pwCF, particularly within the first 3 months of therapy.

Lipid nanoparticles-loaded with toxin mRNA represents a new strategy for the treatment of solid tumors.

Background and rationale: Cancer therapy have evolved remarkably over the past decade, providing new strategies to inhibit cancer cell growth using immune modulation, with or without gene therapy. Specifically, suicide gene therapies and immunotoxins have been investigated for the treatment of tumors by direct cancer cell cytotoxicity. Recent advances in mRNA delivery also demonstrated the potential of mRNA-based vaccines and immune-modulators for cancer therapeutics by utilizing nanocarriers for mRNA delivery. Methods: We designed a bacterial toxin-encoding modified mRNA, delivered by lipid nanoparticles into a B16-melanoma mouse model. Results: We showed that local administration of LNPs entrapping a modified mRNA that encodes for a bacterial toxin, induced significant anti-tumor effects and improved overall survival of treated mice. Conclusions: We propose mmRNA-loaded LNPs as a new class of anti-tumoral, toxin-based therapy.

Development of Phonemically Balanced Passage, Oral Passage, and Nasal Passage in the Punjabi Language.

The primary aim of the study was to develop phonemically balanced passage, Oral passage and Nasal passage in Punjabi language. Development of the passage: The words in the passage were chosen to represent the way sounds are distributed in spoken Punjabi language, and the relative phonemic distribution of each word inside each paragraph matched how frequently each sound occurs in Punjabi. The paragraph was constructed using words that were rated as extremely familiar and familiar. The developed passages were given to five speech-language pathologists for the purpose of content validation. 100 people with normal hearing between the ages of 18 and 25 were enrolled in the study (50 female and 50 male). Each subject's nasalence was measured using a Nasometer. The individuals were given passages written in Punjabi to read, and their nasalence scores for each text were recorded. The nasalance mean for Punjabi phonemically balanced passage was 36.41 ± 4.61% and 38.57 ± 4.22% in male and female subjects. The Punjabi oral passage mean were 27.36 ± 4.14% and 28.46 ± 4.01% in male and female subjects. The means for Punjabi nasal passage were 46.15 ± 4.09% in male subjects and 47.04 ± 4.91% in the female subjects. The Intraclass correlation coefficient for Female and male subjects for the Punjabi Phonemically balanced passage, Punjabi oral passage, Punjabi nasal passage were 0.904, 0.945; 0.807, 0.909, and 0.956, 0.913 respectively. The developed passages have good test retest reliability and their normative scores can be used for assessment of different resonance disorders.

Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model.

BACKGROUND: Treatment of some blood cancers with T cells that express a chimeric antigen receptor (CAR) against CD19 have shown remarkable results. In contrast, CAR-T cell efficacy against solid tumors has been difficult to achieve. METHODS: To examine the potential of CAR-T cell treatments against ovarian cancers, we used the mouse ovarian cancer cell line ID8 in an intraperitoneal model that exhibits disseminated solid tumors in female C57BL/6J mice. The CAR contained a single-chain Fv from antibody 237 which recognizes a Tn-glycopeptide-antigen expressed by ID8 due to aberrant O-linked glycosylation in the absence of the transferase-dependent chaperone Cosmc. The efficacy of four Tn-dependent CARs with varying affinity to Tn antigen, and each containing CD28/CD3ζ cytoplasmic domains, were compared in vitro and in vivo in this study. RESULTS: In line with many observations about the impact of aberrant O-linked glycosylation, the ID8Cosmc knock-out (ID8Cosmc-KO) exhibited more rapid tumor progression compared with wild-type ID8. Despite the enhanced tumor growth in vivo, 237 CAR and a mutant with 30-fold higher affinity, but not CARs with lower affinity, controlled advanced ID8Cosmc-KO tumors. Tumor regression could be achieved with a single intravenous dose of the CARs, but intraperitoneal administration was even more effective. The CAR-T cells persisted over a period of months, allowing CAR-treated mice to delay tumor growth in a re-challenge setting. The most effective CARs exhibited the highest affinity for antigen. Antitumor effects observed in vivo were associated with increased numbers of T cells and macrophages, and higher levels of cleaved caspase-3, in the tumor microenvironment. Notably, the least therapeutically effective CAR mediated tonic signaling leading to antigen-independent cytokine expression and it had higher levels of the immunosuppressive cytokine interleukin10. CONCLUSION: The findings support the development of affinity-optimized CAR-T cells as a potential treatment for established ovarian cancer, with the most effective CARs mediating a distinct pattern of inflammatory cytokine release in vitro. Importantly, the most potent Tn-dependent CAR-T cells showed no evidence of toxicity in tumor-bearing mice in a syngeneic, immunocompetent system.

Versatility of Facial Artery Musculomucosal (FAMM) Flap for Reconstruction of Oral Cavity Defects.

Background and Purpose: The Facial Artery Musculomucosal (FAMM) flap for reconstruction of oral cavity defects is being popularized in recent years due to its obvious advantages. The aim of our study is to evaluate the cases operated at our institute for the reconstruction of oral cavity defects using FAMM flap and assess their outcomes. Method: In this retrospective study, we included all patients in whom the FAMM flap was used to reconstruct oral cavity defects operated at our institute from January 2017 to December 2020. From the available records, patients' data like age, sex, diagnosis, treatment plan, complications, flap viability, and need for pedicle revision were retrieved and tabulated. Results: FAMM flap was used in ten patients (8 male, 2 female) with ages ranging from 40 to 54 years. In six patients with superior defects e.g., maxilla/palate, retrograde FAMM flap was used and in the other 4 patients with inferior defects e.g., tongue/ floor of the mouth, antegrade FAMM flap was used. None of the patients developed complications like flap failure/necrosis or dehiscence. The donor site healed uneventfully in all patients. Conclusion: FAMM flap offers various advantages for oral cavity reconstruction including mucosa reconstruction with alike mucosal tissue, muscle portion providing bulk, minimal donor site morbidity along with easier harvesting approach. There are no associated significant long-term complications if the technique is properly followed. FAMM should be considered a viable option for the reconstruction of a variety of oral cavity defects.