Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway.

Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20-80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.

Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis.

Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was evaluated. CP exhibited potent radiosensitization in lung cancer cells via inhibition of Nrf-2 pathway, leading to elevation of oxidative stress. Transcriptomic studies revealed significant modulation of pathways related to ferroptosis, fatty acid and glutathione metabolism. Consistent with these findings, CP treatment followed by radiation exposure showed characteristic features of ferroptosis in terms of mitochondrial swelling, rupture and loss of cristae. Ferroptosis is a form of regulated cell death triggered by iron-dependent ROS accumulation and lipid peroxidation. In combination with radiation, CP showed enhanced iron release, mitochondrial ROS, and lipid peroxidation, indicating ferroptosis induction. Further, iron chelation, inhibition of lipid peroxidation or scavenging mitochondrial ROS prevented CP-mediated radiosensitization. Nrf-2 negatively regulates ferroptosis through upregulation of antioxidant defense and iron homeostasis. Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.

Mitochondrial-targeted curcumin inhibits T-cell activation via Nrf2 and inhibits graft-versus-host-disease in a mouse model.

Anti-inflammatory and immune suppressive agents are required to moderate hyper-activation of lymphocytes under disease conditions or organ transplantation. However, selective disruption of mitochondrial redox has not been evaluated as a therapeutic strategy for suppression of T-cell-mediated pathologies. Using mitochondrial targeted curcumin (MitoC), we studied the effect of mitochondrial redox modulation on T-cell responses by flow cytometry, transmission electron microscopy, transcriptomics, and proteomics, and the role of Nrf2 was studied using Nrf2- /- mice. MitoC decreased mitochondrial TrxR activity, enhanced mitochondrial ROS (mROS) production, depleted mitochondrial glutathione, and suppressed activation-induced increase in mitochondrial biomass. This led to suppression of T-cell responses and metabolic reprogramming towards Treg differentiation. MitoC induced nuclear translocation and DNA binding of Nrf2, leading to upregulation of Nrf2-dependent genes and proteins. MitoC-mediated changes in mitochondrial redox and modulation of T-cell responses are abolished in Nrf2- /- mice. Restoration of mitochondrial thiols abrogated inhibition of T-cell responses. MitoC suppressed alloantigen-induced lymphoblast formation, inflammatory cytokines, morbidity, and mortality in acute graft-versus-host disease mice. Disruption of mitochondrial thiols but not mROS increase inculcates an Nrf2-dependent immune-suppressive disposition in T cells for the propitious treatment of graft-versus-host disease.

Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis.

Increasing use of ionizing radiation (IR) in medicine, industry, agriculture and research ensues potential health hazards if not used properly or contained effectively. However, radioprotectors which are effective in clinical and/or accidental radiation exposures are still elusive. In this direction, we have explored the radioprotective potential of Withaferin A, a plant withanolide, which was recently shown to be safe and well tolerated in cancer patients in a clinical trial and is also known to be a radio-sensitizer in cancer cells. Our results show that, Withaferin A (WA) protected only normal lymphocytes, but not cancer cells, against IR-induced apoptosis and offered radioprotection even when added post-radiation exposure. WA treatment led to significant inhibition of IR-induced caspase-3 activation and decreased IR-induced DNA damage to lymphocytes and bone-marrow cells. WA reduced intracellular ROS and GSH levels and only thiol based anti-oxidants could abrogate the radio-protective effects of WA, indicating a crucial role of cellular/protein thiols in its biological activity. The inability of WA-glutathione adduct to offer radioprotection further underscored the role of cellular thiols. WA induced pro-survival transcription factor, Nrf-2, and expression of cytoprotective genes HO-1, catalase, SOD, peroxiredoxin-2 via ERK. Further, WA administration could rescue mice against radiation induced mortality, DNA damage, increase in micro-nucleated polychromatic erythrocytes (mn-PCEs) and increased ratio of polychromatic erythrocytes (PCEs) to Normochromatic Erythrocytes (NCEs) in bone-marrow, demonstrating its potent in vivo the radio-protective efficacy. In conclusion, WA selectively protects normal cells against IR-induced apoptosis via activation of cytoprotective Nrf-2 pathway.

Defensive Mechanisms in Cucurbits against Melon Fly (Bactrocera cucurbitae) Infestation through Excessive Production of Defensive Enzymes and Antioxidants.

Melon fly (Bactrocera cucurbitae) is the most common pest of cucurbits, and it directly causes damage to cucurbit fruits in the early developmental stage. The infection of fruit tissues induces oxidative damage through increased generation of cellular reactive oxygen species. The effects of melon fly infestation on the production of defensive enzymes and antioxidant capabilities in five cucurbit species, namely, bottle gourd, chayote, cucumber, snake gourd, and bitter gourd, were investigated in this study. The total phenolic and flavonoid content was considerably higher in melon fly infestation tissues compared to healthy and apparently healthy tissues. The chayote and bottle gourd tissues expressed almost 1.5- to 2-fold higher phenolic and flavonoid contents compared to the tissues of bitter gourd, snake gourd, and cucumber upon infestation. Defensive enzymes, such as peroxidase (POD), superoxide dismutase (SOD), polyphenol oxidase (PPO), and catalase (CAT), were high in healthy and infected tissues of chayote and bottle gourd compared to bitter gourd, snake gourd, and cucumber. The activity of POD (60-80%), SOD (30-35%), PPO (70-75%), and CAT (40-50%) were high in infected chayote and bottle gourd tissue, representing resistance against infestation, while bitter gourd, snake gourd, and cucumber exhibited comparatively lower activity suggesting susceptibility to melon fly infection. The antioxidant properties were also high in the resistant cucurbits compared to the susceptible cucurbits. The current research has enlightened the importance of redox-regulatory pathways involving ROS neutralization through infection-induced antioxidative enzymes in host cucurbit resistance. The melon fly infestation depicts the possible induction of pathways that upregulate the production of defensive enzymes and antioxidants as a defensive strategy against melon fly infestation in resistant cucurbits.

Evaluation of Sagittal Root Positions and Bone Perforation in Anterior Teeth Using Cone Beam Computed Tomography: An Observational Study.

Cone beam computed tomography (CBCT) and virtual implant help clinicians assess implant positioning with nearby vital structures and plan implant surgical procedures. Thus, the current study aims to evaluate the anterior sagittal root position and assess labial bone perforations in CBCT images. This study was carried out using CBCT scans of 140 samples involving 1338 teeth. The Digital Imaging and Communications in Medicine (DICOM) files were imported into Carestream 3-dimensional imaging software for analysis. All measurements were made in the appropriate section slice of 200-µm thickness in a darkened room. A standardized orientation was established by 2 examiners. The sagittal root positions (SRPs) were assessed in maxillary and mandibular anterior teeth. Labial bone perforation (LBP) was assessed using tapered implants in the virtual implant software. Overall, Class I SRP was highest (81.48% and 38.49%, respectively) in both the sextants. The SRP for Class I was most prevalent in canine teeth in both arches (87.96% and 56.45%, respectively), followed by incisors in other types in the maxillary arch. In the mandibular arch, both incisors were in Class IV and I relationships. The overall LBP was 4.26% and was more likely in the mandibular arch (5.64%) than in the maxillary arch (2.8%). The mandibular central incisors showed the highest rate of perforation (8.5% to 11.93%). The SRP and LBP did not show a statistically significant difference between the right and left sides in both arches. The correlation coefficient between SRP and LBP showed a statistically significant result (P < .01). Class I SRP was the most prevalent in maxillary and mandibular arches. Significantly more perforations occurred with mandibular anterior teeth and in Class IV SRP types (approximately 10% to 30%), which suggests that implant placement requires careful presurgical planning and regenerative approaches or delayed implant placement may be considered.

Epigenetic mechanisms of Groucho/Grg/TLE mediated transcriptional repression.

The repression of transcription, through the concerted actions of tissue specific DNA binding proteins, Polycomb repressor complexes, and DNA methylation, is essential for maintaining stem cell pluripotency and for cell fate specification in development. In this report, we show that recruitment of the co-repressor protein Grg4 to a Pax DNA-binding site displaces the adaptor protein PTIP and a histone H3K4me complex. Grg4 recruits the arginine methyltransferase PRMT5 to chromatin resulting in symmetric H4R3 dimethylation. PRMT5 is essential for recruiting Polycomb proteins, in a Pax2/Grg4 dependent manner, which results in H3K27 methylation. These data define the early epigenetic events in response to Pax/Grg mediated gene repression and demonstrate that a single DNA binding protein can recruit either an activator or a repressor complex depending on the availability of Grg4. These data suggest a model for understanding the initiation of Groucho/Grg/TLE mediated gene silencing.

Role of fatty-acid synthesis in dendritic cell generation and function.

Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4(+) and CD8(+) T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8(+) T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. CONCLUSION: Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH.

Pindborg tumor arising in association with an impacted supernumerary tooth in the anterior maxilla.

Pindborg tumor/Calcifying Epithelial Odontogenic Tumor (CEOT) is a benign epithelial odontogenic tumor which shows locally aggressive behavior and accounts for less than 1% of all odontogenic tumors. The most frequent location is the mandibular premolar and molar area; less frequently the lesion is found in the maxilla. Since histopathology remains the main method for definitive diagnosis, this lesion presents an enigma to a clinician when lesions occur in atypical locations. The authors report a case of CEOT in the maxillary anterior region associated with an impacted supernumerary tooth (mesiodens).

Percutaneous injection of autologous platelet gel accelerate healing in diabetic tibial non union: On going longitudinal study.

INTRODUCTION: In this study the tibial shaft fracture non unions in diabetes mellitus are evaluated with percutaneous autologous platelet gel supplementation to accelerate union are compared with individually matched control group with autologous iliac crest bone marrow aspirate injection. MATERIAL AND METHODS: This present study was carried out on tibial non unions in diabetic patients recruited in an ongoing longitudinal study over a period of 2006 to 2017, treated by one surgeon at one institute, are included in this report. Each of 18 established tibial atrophic, aseptic non unions treated by percutaneous autologous platelets and iliac crest bone marrow aspirate were followed up on regular basis up till 9 months. The healing of non union was assessed clinically by painless full weight bearing and the radiological union was judged by bridging callus formation observed on at least 3 of 4 cortices in anteroposterior and lateral views. RESULTS: Union was observed in 17 (94.4 %) patients of the autologous platelet group. The average time to union was 9.2 weeks (range 8 to 18 weeks) after percutaneous autologous platelet injection (P < 0.0517) .In the control group, union was observed in 14 (77.8 %) patients (P = 0.672). The average time to union following percutaneous bone marrow injection was 11.6 weeks (range 9 to 28 weeks). The proximal 1/3 shaft non union healed comparatively faster than the distal 1/3 shaft tibia (P ≤ 0.0612). No correlation was observed between the comminuted and non comminuted fracture non union (P = 0.789). A significant correlation was noted as regards the non union healing time duration in patients who were on insulin and oral hypoglycemic drugs (P ≤ 0.001) and also about the total duration of diabetes mellitus in years (P ≤ 0.003). CONCLUSION: This investigation showed that percutaneous autologous platelet gel delivery is sufficient method to obtain union in diabetic tibial fracture non unions, which is less invasive procedure than bone marrow injection. The efficacy of this autologous platelets is once again well established and this study reinforced categorically the previously published report by the author.

Efficacy of Self-assembling Peptide P11-4 in Remineralizing In Vitro Caries-like Lesions in Primary Enamel Samples in Combination with Calcium Phosphate-based Remineralization Agents.

Aims and background: The efficacy of self-assembling peptide P11-4 in combination with calcium-phosphate-based remineralization agents in remineralizing caries-like lesions in primary enamel was evaluated using a 21-day pH cycling experiment by Vickers microhardness [Vickers hardness number (VHN)] and scanning electron microscopy (SEM). Materials and methods: A total of 120 primary enamel samples were made to undergo a demineralization cycle to produce caries-like lesions. They were divided into six groups, namely negative control (NC), positive control (P11-4), and four interventional groups in which each of the following calcium-phosphate-based agents were used in combination with P11-4-calcium sucrose phosphate (CSP), bioactive glass (BG), casein phosphopeptides, and casein phosphopeptides with fluoride. A 21-day pH cycling experiment was carried out with alternating demineralization and remineralization phases. The enamel samples were analyzed at baseline, post production of caries-like lesions, and post 21-day pH cycling using Vickers microhardness and SEM. Results were statistically analyzed using repeated measures of analysis of variance (ANOVA), keeping the level of significance at 0.05. Results: Supplementing P11-4 with calcium-phosphate-based agents improved the surface hardness of the demineralized primary enamel samples, among which the fluoridated milk protein-based remineralization agent yielded a statistically significant improvement. Conclusion: P11-4 promoted the regeneration of incipient caries-like lesions. However, there is added benefit when this peptide is used in combination with a fluoridated calcium-phosphate-based agent. Clinical significance: This study would help the clinician compose an effective regimen for the patient to follow at home posttreatment with P11-4, in-office treatment. How to cite this article: Krishnamoorthi A, Shanbhog RS, Godhi BS, et al. Efficacy of Self-assembling Peptide P11-4 in Remineralizing In Vitro Caries-like Lesions in Primary Enamel Samples in Combination with Calcium Phosphate-based Remineralization Agents. Int J Clin Pediatr Dent 2024;17(5):552-557.

Does Platelet-Rich Plasma Deserve a Role in Accelerating the Recovery of Reflex Sympathetic Dystrophy Following Distal Radius Fracture?

Introduction: This study was to evaluate the efficacy of multiple platelet-rich plasma injections in reflex sympathetic dystrophy following distal radius fracture after previous various treatments have failed. Materials and methods: This comparative prospective study was designed for 64 patients of reflex sympathetic dystrophy developed following distal radius fracture, from January 2009 to December 2020 were enrolled in this study. This cohort of patient was given either four multiple subcutaneous platelet-rich plasma injections at weekly interval (n = 32) or two injections in a month with 15 days interval (n = 32). The primary outcome measure assessed with patient rated wrist evaluation questionnaire score. The secondary outcome was a visual analogue scale pain score. The final follow up was at 2 years. p ≤ 0.05 is considered statistically. Results: The patient rated wrist evaluation score for usual and specific activities and EQ-VAS for pain level showed statistically significant greater improvement in group A (42 ± 21%) compared to group B (19 ± 24%), (p = 0.37). Patients also had improvement in wrist movements with no statistically significant differences in both groups. The standard difference in means of all three functional scores was almost similar between both groups A and B (standard difference in means = 0.032; 95% CI 0.236-0.830; p = 0.495), considered clinically meaningful. Conclusion: This study results suggest autologous platelet-rich plasma injections seem to be safe, cost effective, efficacious algorithm treatment for reflex sympathetic dystrophy following distal radius fracture patients where previous treatments have failed.

Txnrd1 as a prognosticator for recurrence, metastasis and response to neoadjuvant chemotherapy and radiotherapy in breast cancer patients.

Thioredoxin reductase 1 (Txnrd1) is known to have prognostic significance in a subset of breast cancer patients. Despite the pivotal role of Txnrd1 in regulating several cellular and physiological processes in cancer progression and metastasis, its clinical significance is largely unrecognized. Here, we undertook a retrospective comprehensive meta-analysis of 13,322 breast cancer patients from 43 independent cohorts to assess prognostic and predictive roles of Txnrd1. We observed that Txnrd1 has a positive correlation with tumor grade and size and it is over-expressed in higher-grade and larger tumors. Further, hormone receptor-negative and HER2-positive tumors exhibit elevated Txnrd1 gene expression. Patients with elevated Txnrd1 expression exhibit significant hazards for shorter disease-specific and overall survival. While Txnrd1 has a positive correlation with tumor recurrence and metastasis, it has a negative correlation with time to recurrence and metastasis. Txnrd1High patients exhibit 2.5 years early recurrence and 1.3 years early metastasis as compared to Txnrd1Low cohort. Interestingly, patients with high Txnrd1 gene expression exhibit a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they experience early recurrence after radiotherapy. Txnrd1High MDA-MB-231 cells exhibit significant ROS generation and reduced viability after doxorubicin treatment compared to Txnrd1Low MCF7 cells. Corroborating with findings from meta-analysis, Txnrd1 depletion leads to decreased survival, enhanced sensitivity to radiation induced killing, poor scratch-wound healing, and reduced invasion potential in MDA-MB-231 cells. Thus, Txnrd1 appears to be a potential predictor of recurrence, metastasis and therapy response in breast cancer patients.

Distinct spectral signatures unfold ECM stiffness-triggered biochemical changes in breast cancer cells.

Cancer progression often accompanies the stiffening of extracellular matrix (ECM) in and around the tumor, owing to extra deposition and cross-linking of collagen. Stiff ECM has been linked with poor prognosis and is known to fuel invasion and metastasis, notably in breast cancer. However, the underlying biochemical or metabolic changes and the cognate molecular signatures remain elusive. Here, we explored Raman spectroscopy to unveil the spectral fingerprints of breast cancer cells in response to extracellular mechanical cues. Using stiffness-tuneable hydrogels, we showed that cells grown on stiff ECM displayed morphological changes with high proliferation. We further demonstrated that Raman Spectroscopy, a label-free and non-invasive technique, could provide comprehensive information about the biochemical environment of breast cancer cells in response to varying ECM stiffness. Raman spectroscopic analysis classified the cells into distinct clusters based on principal component-based linear discriminant analysis (PC-LDA). Multivariate curve resolution-alternating least squares (MCR-ALS) analysis indicated that cells cultured on stiff ECM exhibited elevated nucleic acid content and lesser lipids. Interestingly, increased intensity of Raman bands corresponding to cytochrome-c was also observed in stiff ECM conditions, suggesting mitochondrial modulation. The key findings harboured by spectral profiles were also corroborated by transmission electron microscopy, confirming altered metabolic status as reflected by increased mitochondria number and decreased lipid droplets in response to ECM stiffening. Collectively, these findings not only give the spectral signatures for mechanoresponse but also provide the landscape of biochemical changes in response to ECM stiffening.

Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial.

BACKGROUND: Due to the progressive decline in ß-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). METHODS: In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0-11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. RESULTS: Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (- 1.64) vs. MS (- 1.32); between groups was [- 0.32% (95% CI, - 0.59, - 0.05)], P = 0.0208. Similar reductions were found in FPG [- 13.2 mg/dL (95% CI, - 22.86, - 3.71)], P = 0.0068, and PPG [- 20.83 mg/dL (95% CI, - 34.11, - 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. CONCLUSION: The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. TRIAL REGISTRATION: Clinical Trials Registry of India, CTRI/2021/10/037461.

Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver.

BACKGROUND & AIMS: Immune cells of the liver must be able to recognize and react to pathogens yet remain tolerant to food molecules and other nonpathogens. Dendritic cells (DCs) are believed to contribute to hepatic tolerance. Lipids have been implicated in dysfunction of DCs in cancer. Therefore, we investigated whether high lipid content in liver DCs affects induction of tolerance. METHODS: Mouse and human hepatic nonparenchymal cells were isolated by mechanical and enzymatic digestion. DCs were purified by fluorescence-activated cell sorting or with immunomagnetic beads. DC lipid content was assessed by flow cytometry, immune fluorescence, and electron microscopy and by measuring intracellular component lipids. DC activation was determined from surface phenotype and cytokine profile. DC function was assessed in T-cell, natural killer (NK) cell, and NKT cell coculture assays as well as in vivo. RESULTS: We observed 2 distinct populations of hepatic DCs in mice and humans based on their lipid content and expression of markers associated with adipogenesis and lipid metabolism. This lipid-based dichotomy in DCs was unique to the liver and specific to DCs compared with other hepatic immune cells. However, rather than mediate tolerance, the liver DC population with high concentrations of lipid was immunogenic in multiple models; they activated T cells, NK cells, and NKT cells. Conversely, liver DCs with low levels of lipid induced regulatory T cells, anergy to cancer, and oral tolerance. The immunogenicity of lipid-rich liver DCs required their secretion of tumor necrosis factor α and was directly related to their high lipid content; blocking DC synthesis of fatty acids or inhibiting adipogenesis (by reducing endoplasmic reticular stress) reduced DC immunogenicity. CONCLUSIONS: Human and mouse hepatic DCs are composed of distinct populations that contain different concentrations of lipid, which regulates immunogenic versus tolerogenic responses in the liver.

A split-mouth randomised controlled trial comparing the clinical effects of MVISTA with chorion membrane or connective tissue graft in multiple gingival recessions.

Objectives: Modified form of VISTA (MVISTA), a novel surgical procedure, aims at comprehensive root coverage that maintains the inner continuity of the periosteum and papilla. This technique incorporates any regenerative graft material within the tunnel. The objective of study is to compare the MVISTA for treating multiple adjacent gingival recessions and chorion membranes or grafts of connective tissues. Materials and methods: This is a split-mouth type randomized trial. In this trial total of 18 patients were considered. The patients in this trial had multiple adjacent, gingival recessions of Miller's Classes I/II, and they were randomized to either the MVISTA with chorion membrane (test) or connective tissue graft (CTG) (control) group. A baseline and one year after surgery were considered for recording to mean root coverage (MRC), complete root coverage (CRC), and clinical periodontal parameters. An intragroup comparison was made. Results: The intragroup comparison of recession depth baseline and 12 months after-surgery record found a significant difference between the two groups (P = 0.00). In the postoperative condition, the depth of recession reduction was higher in the test group than in the control group. However, from a statistical perspective, the difference was insignificant (P > 0.05). At the end of the year, it was found that the width of the keratinized tissue had increased significantly (P < 0.05). The MRC in the test group was significantly higher (91.33 %±8.17 %) than that in the control group (89.46 %±11.22 %) (P > 000). At the end of 1 year, the test group showed 66.67 % CRC compared to 44.44 % in the control group. The gingival phenotype displayed statistically significant improvement in the test group (p = 0.004). PD and CAL showed statistically nonsignificant outcomes (P > 0.05). Conclusions: As far as multiple adjacent gingival recession treatment is concerned, MVISTA with chorion membrane treatment enhanced the gingival phenotype, restored complete root coverage (66.6%), and increased the width of keratinized tissue. CTG and CM demonstrated good root coverage results; the latter might be used as a substitute graft to treat multiple recessions.

Is There a Case for Case-Based Learning in Pharmacology?

Background In a didactic lecture (DL), students listen, take notes, and passively accept the knowledge. Case-based learning (CBL) uses clinical cases for active learning and productive outcome. Although some studies have shown that DL is less effective than CBL, the results were inconclusive. Hence, this study aimed to evaluate the effectiveness of CBL in pharmacology. Methodology This study involved 80 second-year medical students divided into two groups. The results of post-test scores and retention test one month later were compared between the groups using multiple-choice questions. Results DL showed statistically significant better outcomes in immediate learning compared to CBL in both groups (p = 0.000 and 0.002). Although there were slightly better retention scores for CBL compared to DL in both groups, it was not statistically significant. Conclusions DL showed significantly better immediate learning outcomes compared to CBL, with no difference in long-term outcomes for both teaching-learning methods. Hence, DL continues to be the gold standard for teaching pharmacology.