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Allium wallichii (A. wallichii) Kunth, is an underutilized rare medicinal plant species with several beneficial ethnomedicinal health promotion activity Moreover, being so popular in both ethanobotanicals and traditional herbal system, still the plant is very less studied for phytochemical and nutritional composition analysis. Therefore, phytochemical and nutritional composition analysis of A. wallichii leaves are set as the main objective of the current work. In this context powder of A. wallichii leaves was subjected for the nutritional analysis and the extract was subjected to thin layer chromatography analysis for fingerprinting of various compounds. In this context, we have found presence of several health promoting nutraceutical bioactives and phytochemicals compounds. In conclusion the traditional utilization of plant in ethnomedicine for nutraceutical and medicinal purpose was attributed due to presence of nutraceutical bioactives and phytochemicals compounds.

Supplementary Table S1. Characteristics of study population (n=84). Supplementary Figure S1. Validation of cIAP1 antibody by immunohistochemistry. Supplementary Figure S2. Sensitivity of HNSCC cells to radiation or LCL161 as a single agent. Supplementary Figure S3. LCL161 does not alter the phosphorylation of STAT3, AKT and ERK in HNSCC cells. Supplementary Figure S4. Altered treatment schedule of LCL161 and radiation does not affect the radiosensitivity of Cal27 cells. Supplementary Figure S5. LCL161 and radiation do not substantially increase tumor cell expression of TNFα(after 24-48 hrs) but does increase TNFα secretion, and TNFα potentiates radiation mediated-apoptosis in tumor cells. Supplementary Figure S6. Kaplan-Meier survival curves demonstrating percent of mice free from tumor doubling are shown for both Cal27 and FaDu xenografts.α

PDF file, 2741KB, YM155 treatment induces survivin migration to nucleus in a time-dependent manner. CAL27-CisR cells were treated with YM155 (10 nM) for different time intervals and survvin localization was examined by staining these cells with survivin (red), β-catenin (green, membrane staining), and DAPI (blue, nucleus).

PDF file, 34KB, Patient tumor characteristics (Group 1).

Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC, and it often leads to local and distant failure. In this study, we showed that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in human papilloma virus–negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin-resistant cells (CAL27-CisR) as compared with its parent cells (CAL27). Therefore, we hypothesized that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its antiapoptotic function. In a severe combined immunodeficient mouse xenograft model, YM155 significantly enhanced the antitumor and antiangiogenic effects of cisplatin, with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of the chemotherapy in HNSCC. Mol Cancer Ther; 11(9); 1988–98. ©2012 AACR.

PDF file, 1581KB, HNSCC cell line characteristics.

PDF file, 828KB, YM155 treatment does not significantly affect mice body weight. Mice weights were measured on days 9, 18, 27 and 36.

PDF file, 2045KB, Patient tumor characteristics (Group 2).

PDF file, 995KB, YM155 inhibits tumor cell proliferation in a dose-dependent manner. Cell proliferation in tumor cells (UM-SCC-74A or CAL27-CisR) or human oral keratinocytes (HOK) was assessed by MTT assay after 72 hrs.

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PDF file, 5124KB, YM155 and cisplatin combination treatment significantly inhibits tumor cell motility. Tumor cell motility was examined by scratch assay.

PDF file, 839KB, YM155 and cisplatin combination treatment significantly inhibits tumor cell proliferation. UM-SCC-74A cells were treated with YM155 or cisplatin (CDDP) alone or in combination. After 72 hrs, cell proliferation was assessed by MTT assay.

Purpose:VSIR is a novel immune checkpoint protein whose expression on tumor cells across cancers remains largely uncharacterized. Here we purposed to decode the pan-cancer biologic and clinical significance of VSIR overexpression in the tumor compartment.Experimental Design:We performed multi-omics integrative analyses of 9,735 tumor samples to identify cancers with non-leukocytic expression of VSIR (VSIR High), followed by association with overall survival and immune cell infiltration levels. Orthogonal assessments of VSIR protein expression and lymphocytic infiltration were performed using quantitative immunofluorescence (QIF).Results:Integrative modeling identified a subset of cancer types as being enriched for VSIR High tumors. VSIR High tumors were associated with significantly poorer overall survival in immunogenic ovarian serous adenocarcinoma (SA) and oral cavity squamous cell carcinoma (SCC). QIF assessments in an independent validation cohort confirmed overexpression of VSIR as being associated with poorer overall survival within immunogenic oral cavity SCC. VSIR overexpression was associated with lower CD4 helper T-cell infiltration in both ovarian SA and oral cavity SCC, but did not impact CD8 T-cell infiltration. VSIR overexpressing tumors in both cancer types exhibited significantly higher STAT3 signaling activity. Pharmacologic inhibition of STAT3 signaling resulted in dose-dependent reduction of VSIR expression in ovarian SA and oral cavity SCC cells.Conclusions:The STAT3-VSIR axis is a potentially significant immunomodulatory mechanism in oral cavity and ovarian cancers, whose activation is associated with poorer survival and an immune microenvironment marked by decreased CD4 helper T-cell activity. The role of VSIR as a tumor-intrinsic modulator of resistance to immunotherapy warrants further exploration.

Supplementary Date from Multi-scale Pan-cancer Integrative Analyses Identify the STAT3-VSIR Axis as a Key Immunosuppressive Mechanism in Head and Neck Cancer

Objective: Insulin resistance is a common link between diabetes mellitus (DM) and dementia. The current work emphasizes the effect of linagliptin on dementia with its neuroprotective effects, which occur directly at the neuronal level, as GLP-1 receptors are exclusively expressed in neurons. background: Insulin resistance is common cause of two commonly occurring diseases i.e. Diabetes mellitus (DM) and dementia. Method: The objective of the study was to formulate linagliptin-loaded polymeric nanosuspension (LS) by nanoprecipitation method and further study their pharmaceutical, pharmacodynamics, scintigraphic, and neuroprotective effects following nose-to-brain delivery in the rat model of dementia. objective: The current work emphasizes the effect of linagliptin against dementia with its neuroprotective effects, which occurs directly at the neuronal levels as GLP-1 receptors are exclusively expressed in neurons. Results: Developed LS were spherical with z-average (250.7 nm), charge (-16.3 mV), % entrapment efficiency (95.8 ± 1.45 %), and % drug loading (35.78 ± 0.19 %). In-Vitro dissolution rate (88.56 ± 1.24 %) and ex vivo permeation (81.59 ± 1.06 %) of LS showed a better-sustained release profile than pure linagliptin. The spatial learning/memory in the treated group of Sprague–Dawley rats were significantly improved compared with those in the control group. method: The objective of the study was to formulate Linagliptin loaded polymeric nanosuspension (LS) by nanoprecipitation method and further studied their pharmaceutical, pharmacodynamics, scintigraphic and neuroprotective effects following nose-to-brain delivery in the rat model of dementia. Conclusion: Histopathological study of LS produced no toxicity or structural damage to the nasal mucosa. Optimum pharmaceutical characterization results improved pharmacodynamic studies/ histopathological data, and gamma-scintigraphic images proved that polymeric nanosuspensions stand out as well-appreciated approaches to deliver linagliptin more efficiently to the brain via intranasal route, thereby enhancing the neuroprotective efficacy in dementia. result: Developed LS were spherical with z-average (250.7 nm), charge (-16.3 mV), % entrapment efficiency (95.8 ± 1.45 %), and % drug loading (35.78 ± 0.19 %). In-Vitro dissolution rate (88.56 ± 1.24 %) and ex-vivo permeation (81.59 ± 1.06 %) of LS showed a better-sustained release profile than pure linagliptin. The spatial learning/memory of rats in the treated group significantly improved compared with those in the control group. Histopathological study of LS produced no toxicity or structural damage to nasal mucosa. . conclusion: Optimum pharmaceutical characterization results, improved pharmacodynamic studies/ histopathological data and gamma-scintigraphic images proved that polymeric nanosuspension stand out as well appreciated approach to deliver linagliptin more efficiently to the brain via intranasal route, thereby enhancing neuroprotective efficacy in dementia

Abstract: Diabetic retinopathy is a posterior eye disorder in which damage occurs to the light sensitive retina due to diabetes mellitus. This disorder specifically affects people aged between 18-64 with type ІІ diabetes. This disease progresses through different pathophysiological pathways, which include oxidative stress, inflammation, stimulation of the growth factor in the eye’s vasculature, isoforms of protein kinase C, and also the activation of the hexosamine pathway. It starts as micro aneurysms and advances in complicated stage, which results in retinal detachment. Treatment of posterior eye diseases has complications due to the structural design of the eye and physiological barriers present. The current treatment approach involves the use of intravitreal anti- VEGFs, corticosteroids implants, laser and surgery; these treatment methods have drawbacks attributed to them despite their benefits. The development of a robust delivery system with minimal or no invasion to tackle the issues of diabetic retinopathy will be of considerable benefit to patients having diabetic retinopathy; the dependency on ophthalmologists for multiple injections will significantly reduce and provide a promising approach in drug delivery. In this review article, the authors provided information related to existing treatment methods available for diabetic retinopathy, the most significant among which is nanotechnology approach through which local delivery via the ocular route to posterior eye can be achieved. It also possesses the various carriers studied for the non-invasive approach for retinal delivery of medicaments. Non-invasive approach for delivery of drugs can be considered as potential for the treatment of diabetic retinopathy.

Neurodegenerative disorders occur when nerve cells in the brain or peripheral nervous system partial or complete fail in their functions and sometimes even die due to some injuries or aging. Neurodegenerative disorders such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), have been majorly resulted due to degeneration of neurons and neuroinflammation progressively. There are many similarities that correlates both AD and PD on a cellular and sub-cellular level. Therefore, a hope for therapeutic advancement for simultaneous upgradation in both the diseases are directly depending on the discovery of common mechanism at molecular and cellular level. Recent and past evidences from scientific literature supporting the efficacy of plants flavonoids in treatment and protection of both AD and PD. Further, dietary flavones, specially Heptamethoxyflavone, Kaempferitrin, Vitexin and Amentoflavone gains recently much more attention for producing many health beneficiary effects including neuroprotection. Despite of these evidence a detailed updated overview of neuroprotective effects against both AD and PD by Heptamethoxyflavone, Kaempferitrin, Vitexin and Amentoflavone are still missing. In this context several published studies were assessed by using various online electronic search engines/databases to meet the objective from 1981 to 2021 (Approx. 224). Therefore, present review was designed to deliver the detailed description on these flavones including therapeutic benefits in AD, PD and other CNS complications with critical analysis on underlying mechanisms.

Targeting inhibitor of apoptosis proteins (IAP) with second mitochondria-derived activator of caspase (SMAC) mimetics may promote cancer cell death. We tested whether cIAP1 predicts poor prognosis in head and neck squamous cell carcinoma (HNSCC) and whether a novel Smac-mimetic, LCL161, could radiosensitize human papillomavirus–positive (HPV+) and -negative (HPV−) HNSCC. The association of BIRC2 (encoding cIAP1) mRNA level with HPV status in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) database. cIAP1 was assessed by IHC on an HNSCC tissue microarray (TMA, n = 84) followed by correlation analysis with HPV status and patient outcomes. Human cell culture and animal models of HNSCC were used to analyze the outcome and molecular characteristics following radiotherapy in combination with LCL161. cIAP1 expression is increased in HPV− compared with HPV+HNSCC tumors in the TCGA database. In our TMA, cIAP1 was overexpressed in HNSCC compared with normal tissues (P = 0.0003) and associated with a poor overall survival (P = 0.0402). cIAP1 levels were higher in HPV− than that in HPV+HNSCC tumors (P = 0.004) and patients with cIAP1+/HPV− HNSCC had the worst survival. LCL161 effectively radiosensitized HPV− HNSCC cells, which was accompanied with enhanced apoptosis, but not HPV+ HNSCC cells. Importantly, LCL161 in combination with radiotherapy led to dramatic tumor regression of HPV− HNSCC tumor xenografts, accompanied by cIAP1 degradation and apoptosis activation. These results reveal that cIAP1 is a prognostic and a potential therapeutic biomarker for HNSCC, and targeting cIAP1 with LCL161 preferentially radiosensitizes HPV− HNSCC, providing justification for clinical testing of LCL161 in combination with radiation for patients with HPV− HNSCC.

Objective: The main objective of the study was to develop gliptin loaded polymeric nanomicelles by direct dissolution method. The comparative evaluation studies were performed to study the effect of polymer concentration on particle size, entrapment efficiency, loading capacity and drug release of the formulation. Methods: Gliptin loaded polymeric nanomicelles were prepared by the direct dissolution method. The formulations were prepared by varying the concentration of polymer and drug concentration was kept constant in all the formulations. The concentration of polymer (pullulan) was maintained 0.1%, 0.5% 1% in formulation F-1, F-2 and F-3, respectively. The effect of polymer concentration on mean particle size, zeta potential, % entrapment efficiency, % loading capacity and in vitro drug release was studied. Results: The optimized nanoformulation was obtained with pullulan 0.1% concentration with a mean particle diameter of 368.2nm and zeta potential value (-7.96mV) indicating greater stability. Conclusion: Hence F-1 was considered to be the best formulation for the preparation of gliptin loaded polymeric nanomicelles. Hence, it can be concluded that polymeric nanomicellar approach can be beneficial to improve the bioavailability and poor permeability of class III drugs like gliptins and thus can be a better approach for controlled drug delivery.

Objective To identify predictors of overall survival (OS) and to stratify patients according to significant prognostic variables. Methods A retrospective study of 274 consecutive patients with primary Oral Cavity Squamous Cell Carcinoma. Kaplan-Meier, Cox proportional hazard models, and recursive partitioning analysis (RPA) were used for analysis of OS. These results were further validated using National Cancer Database cohort of 21 895 patients. Results Median OS was 3.65 years. T-classification and N-classification, alcoholic beverages/week, age, and adjuvant treatment were significant predictors of OS. RPA identified high-risk subpopulations: N0-1 patients with CCI ≥ 4.5 and N2-3 patients ordered by those not receiving adjuvant treatment, those with T3-4 disease despite adjuvant therapy, and those having T1-2 disease with adjuvant therapy. Conclusions This study utilized significant prognostic indicators and RPA to highlight the importance of age, N-classification, T-classification, comorbidity, and adjuvant therapy in conjunction with American Joint Committee on Cancer staging to improve preoperative counseling.

OBJECTIVES To elucidate predictive factors in the perioperative period resulting in gastrostomy tube (G-tube) dependence for patients undergoing primary surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) in the modern era. METHODS Two hundred and thirty patients with known OPSCC treated with primary surgery were screened and selected from a retrospective database spanning from 2002 to 2012 at The Ohio State University Wexner Medical Center (Columbus, Ohio), with univariable and multivariable logistic regression modeling used to determine independent predictive factors resulting in G-tube dependence (defined as tube persistence/presence 1 year after surgery). RESULTS Surgical approach, baseline characteristics, tumor (T)-nodal-metastasis stage, human papillomavirus status, extent of tissue resected, surgical complications, reconstructive technique, preoperative G-tube presence, and adjuvant treatment were recorded. Patients undergoing open surgery for OPSCC without adjuvant treatment had 42.9% G-tube dependence (44.6% with adjuvant chemoradiation [CRT]) compared to 0% for those undergoing transoral nonrobotic surgery (8.1% with adjuvant CRT) and 0% for those undergoing transoral robotic surgery (10.3% with adjuvant CRT). In multivariable analysis, greater than 25% of the oral tongue resected (odds ratio [OR] 12.29; P = 0.03), an open surgical approach (OR 5.72; P

Objective: Dipeptidyl peptidase-4 (DPP-4) inhibitors are the oral antidiabetics that inhibits the enzyme DPP-4. The main aim of study was to formulate, statistically optimize and characterize the p...