Chemopreventive Efficacy of Sulindac Sulfone as a Selective Apoptotic Antineoplastic Drug in Human Head and Neck Squamous Cell Carcinoma Cell Lines: A Systematic Review.

Sulindac sulfone, an active metabolite of sulindac, a non-steroidal anti-inflammatory drug, has good anti-inflammatory potential. The antineoplastic effect of sulindac sulfone is mediated through a cyclooxygenase inhibitory mechanism, followed by apoptosis and inhibition of cell proliferation. Mounting studies have explored the anti-neoplastic effect of sulindac sulfone in various types of cancers in a dose-dependent manner. In this backdrop, we have conducted a systematic review to evaluate the efficacy and dose of sulindac sulfone as an anti-neoplastic agent in human head and neck squamous cell carcinoma cell lines (HNSCCs). In this study, we used a systematic literature review approach, and articles were searched in PubMed, and Medline with the keywords "sulindac sulfone," "anti-neoplastic activity," "chemopreventive," and "head and neck squamous cell carcinoma". A hand-search of journals was also performed. Articles were reviewed and analyzed. The analysis reveals that, based on the in vitro studies on various tumor models, the optimum concentration of sulindac sulfone which elicits anti-neoplastic effects is 200-800 µM. The anti-neoplastic effect is mediated through inhibition of cell proliferation and apoptosis. The results of our systematic review show that the anti-neoplastic activity of pharmacologic Sulindac sulfone is part of its dose-dependent activity, which can be safely employed in the therapy for human HNSCCs and would be responsible for a beneficial outcome of the treatment.

Cemento-Ossifying Fibroid Epulis in the Posterior Maxilla.

Cemento-ossifying fibroma is a benign fibro-osseous lesion arising from the periodontal ligament and has the potential to form cementum and bone in the periodontal ligament. Cemento-ossifying fibroma is a painless, pedunculated, or sessile, smooth exophytic growth arising attached to the gingival tissues. We present a case of cemento-ossifying fibroid epulis in the posterior maxilla attached to the interdental gingiva between the 26 and 27 region buccally in a 52-year-old female patient managed with surgical excision of the lesion, extraction of the involved teeth, curettage, and palatal obturator while under general anesthesia. The patient was followed up post-operatively, healing was satisfactory, there were no signs of infection, and no recurrence was noted in the six-month follow-up period.

Evaluation of Knowledge, Attitude, and Practice (KAP) of Artificial Intelligence Among Dentists and Dental Students: A Cross-Sectional Online Survey.

BACKGROUND: Artificial intelligence (AI) is the process by which it is possible to program computers to mimic human thoughts. AI and its subsets machine learning and deep learning have been developed to analyze complicated data gathered from many sources using algorithms built into decision support systems. It has been widely used in the field of dentistry. AIM: The study aimed to evaluate the knowledge, attitude, and practice (KAP) of AI among dental students and dentists. METHODOLOGY: The present study is a descriptive cross-sectional online survey that was carried out among dentists and dental students in South India. A self-structured, close-ended questionnaire that was administered that consisted of 25 questions was included. The questions were circulated through Google Forms (Google LLC, Mountain View, California, United States), and it was circulated among the study participants through online mode. The data were collected systematically, and SPSS Statistics version 22.0 (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.) was used for data analysis. RESULTS: One thousand (595 dental surgeons and 405 dental students) participated in the study through Google Forms. Among these, 700 (70%) were females and 300 (30%) were males. In the study group, 635 (63.5%) were aware of AI, and 365 (36.5%) were not aware (p-value 0.000). Among the 21 questions used to assess the KAP, 14 questions were significant with a p-value less than 0.05. More than 60% agreed that the dental curriculum has to be updated with AI. About 269 (26.9%) agreed that AI will replace the role of dentists in the future. There were no significant results in comparing dental surgeons and dental students. CONCLUSION: The present study showed that the KAP among dental surgeons and dental students was the same. They believe that the dental curriculum has to be updated with AI. This study shows that there is a lack of knowledge about deep learning models and websites used for AI among dentists. Thus, it is necessary to include evidence-based teaching and training about the application of AI in dental practice to improve the future of dentistry.

Consanguineous marriage as a key indicator of isolated congenital dental anomaly among South Indian population - A cross-sectional study.

Background: Orofacial anomalies occur due to incomplete fusion of developmental lines in the head and neck region. Dental anomalies regarded as the most common orofacial anomalies either in isolated or syndromic forms arise due to genetic and environmental factors. Among genetic influences, consanguineous marriages are considered as a significant predisposition factor in the transmission of congenital defects and several autosomal recessive diseases from one generation to other with an increased risk of detrimental effects on offspring. Aim: The present study was aimed to evaluate the prevalence and significant association between consanguinity and isolated dental anomalies with that of nonconsanguineous parents among south-Indian population. Methodology: A total of 116 participants with and without dental anomalies in isolated form pertaining to tooth size, shape, altered morphology, number and eruption were selected followed by brief case history. Participants with a positive history of consanguinity were categorized as Group A while others were categorized under Group B. Results: Sixty-four out of 116 participants (55.17%) showed positive consanguinity (Group A) among which 18 females (56%) and 14 males (44%) presented with isolated dental anomalies. 12 females (66.6%) and 9 males (64.2%) in Group A showed significance with first cousin (P = 0.00204) whereas no significance was observed in other consanguinity type (P = 0.7287). Nonetheless, the overall frequency of isolated dental anomalies was slightly higher in Group A than Group B that was statistically significant (P = 0.0213). Conclusion: A positive correlation between dental anomalies among offspring of consanguineous marriages revealed such prevalence may be attributed to increased risk of recessive deleterious gene expression or defective allele carried to offspring.

Self-assembled materials from cellulose nanocrystals conjugated with a thermotropic liquid crystalline moiety.

Manipulating molecular and supramolecular interactions within cellulose nanocrystals (CNCs) to introduce different levels of assemblies combined with multiple functionalities is required for the development of degradable smart materials from renewable resources. To attain hierarchical structures and stimuli-responsive properties, a new class of liquid crystalline cellulosic hybrid materials is synthesized. Herein, main-chain rigid-rod-like oxidized cellulose (CNC-COOH) is prepared from a Cellulose Whatman filter paper (Cellulose W.P.) by acid hydrolysis and oxidized using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). Thermotropic LC molecule, 4-cyano-4'-hydroxybiphenyl with a 12-methylene spacer (CB12-OH) is grafted onto the carboxylic acid group of CNC-COOH via Steglich esterification. The liquid crystalline functionalized CNCs cellulose nanocrystals (CNC-COO-CB12) are readily soluble in DMSO and ionic liquids. The extent of functionalization and structure of CNC-COO-CB12 are confirmed by solution-state 1H NMR and supported by other characterization techniques. We investigate the interplay of liquid crystalline orientational order of CNCs and cyanobiphenyl (CB12), and the supramolecular hydrogen bonding of CNCs within CNC-COO-CB12 and compare it with CNC-COOH. The introduction of thermotropic CB12 side chains onto rigid-rod CNCs shows the exclusive formation of smectic mesophases from the assemblies of CB12 with the absence of the cholesteric mesophase typically observed from CNC-COOH as verified by temperature-controlled SAXS (T-SAXS). This is further verified by UV-visible and SEM studies that show CNC-COO-CB12 forms smectic domains while CNC-COOH forms a visible light reflecting cholesteric mesophase in dried films. Thus, the interplay of liquid crystalline order of CNCs and CB12 and supramolecular hydrogen bonding of CNCs results in ordered, smectic-mesostructured CNCs for use in stimuli-responsive functional materials.

Do preoperative pancreatic computed tomography attenuation index and enhancement ratio predict pancreatic fistula after pancreaticoduodenectomy?

BACKGROUND: The commonly used predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) have subjective assessment components and can be used only in the postoperative setting. Also, the available objective predictors based on preoperative cross-sectional imaging were not prospectively studied. AIM: To evaluate the accuracy of the pancreatic attenuation index (PAI) and pancreatic enhancement ratio (PER) for predicting CR-POPF following PD and its correlation with pancreatic fat fraction and fibrosis. METHODS: A prospective observational study included patients who underwent PD for benign and malignant pathology of the periampullary region or pancreatic head between February 2019 and February 2021. Patients undergoing extended or total pancreatectomy and those with severe atrophy of pancreatic tissue or extensive parenchymal calcifications in the pancreatic head and neck precluding calculation of PAI and PER were excluded from the study. Preoperatively PAI was measured in the neck of the pancreas by marking regions of interest (ROI) in the non-contrast computed tomography (CT), and PER was measured during the contrast phase of the CT abdomen. Also, the fibrosis score and fat fraction of the pancreatic neck were assessed during the histopathological examination. Demographic, clinical and preoperative radiological indices (PAI, PER) were evaluated to predict CR-POPF. Preoperative pancreatic neck CT indices were correlated with the histopathological assessment of fat fraction and fibrosis. RESULTS: Of the 70 patients who underwent PD, 61 patients fulfilling the inclusion criteria were included in the analysis. The incidence of CR-POPF was 29.5% (18/61). PAI had no association with the development of CR-POPF. Of the preoperative parameters, PER (mean ± standard deviation [SD]) was significantly lower in patients developing CR-POPF (0.58 ± 0.20 vs 0.81 ± 0.44, P = 0.006). The area under the curve for the PER was 0.661 (95%CI: 0.517-0.804), which was significant (P = 0.049). PER cut-off of 0.673 predicts CR-POPF with 77.8% sensitivity and 55.8% specificity. PAI and PER had a weak negative correlation (Strength-0.26, P = 0.037). Also, PER showed a moderately positive correlation with fibrosis (Strength 0.50, P < 0.001). Patients with CR-POPF had a significantly higher incidence of the intraabdominal abscess (50% vs 2.3%, P < 0.001), delayed gastric emptying (83.3% vs 30.2, P < 0.001), and prolonged mean (± SD) postoperative hospital stay (26.8 ± 13.9 vs 9.6 ± 3.6, P = 0.001). CONCLUSION: PER exhibited good accuracy in predicting the development of CR-POPF. PER additionally showed a good correlation with PAI and fibrosis scores and may be used as an objective preoperative surrogate for assessing pancreatic texture. However, ROI-based PAI did not show any association with CR-POPF and pancreatic fat fraction.

Dynamic magnetic field alignment and polarized emission of semiconductor nanoplatelets in a liquid crystal polymer.

Reconfigurable arrays of 2D nanomaterials are essential for the realization of switchable and intelligent material systems. Using liquid crystals (LCs) as a medium represents a promising approach, in principle, to enable such control. In practice, however, this approach is hampered by the difficulty of achieving stable dispersions of nanomaterials. Here, we report on good dispersions of pristine CdSe nanoplatelets (NPLs) in LCs, and reversible, rapid control of their alignment and associated anisotropic photoluminescence, using a magnetic field. We reveal that dispersion stability is greatly enhanced using polymeric, rather than small molecule, LCs and is considerably greater in the smectic phases of the resulting systems relative to the nematic phases. Aligned composites exhibit highly polarized emission that is readily manipulated by field-realignment. Such dynamic alignment of optically-active 2D nanomaterials may enable the development of programmable materials for photonic applications and the methodology can guide designs for anisotropic nanomaterial composites for a broad set of related nanomaterials.

Study on reversal of ABCB1 mediated multidrug resistance in Colon cancer by acetogenins: An in-silico approach.

Multi-Drug Resistance (MDR) exerted by tumor cells is majorly due to the overexpression of ATP Binding cassette transporters such as ABCB1/P-glycoprotein (P-gp). Annonaceous acetogenins (AGEs) exert anticancer activity by strongly inhibiting NADH oxidase of cancer cells. The present in silico study aims at screening a potent MDR inhibitor among acetogenins from the plant Annona muricata. Twenty-four AGEs were selected and screened for their pharmacokinetic properties. An inward facing conformation of P-gp is required for understanding the interaction of AGEs at the drug binding region and hence the human P-gp protein was modeled. The selected compounds were then docked with the ATP binding site and the drug binding site of modeled human P-gp. Annonacin A.1, Annohexocin.1 and Annomuricin E.1 docked better with high MM/GBSA dG binding in the drug binding region as compared with the conventional drugs. These compounds had a better docking score as compared with control inhibitor drugs at the ATP binding region. The complexes were subjected to MD simulation and Annonacin A was stable throughout the simulation period. Therefore, Annonacin A might act as a competitive inhibitor for the chemo drugs for binding at the drug binding region of P-gp. Hence it is capable of decreasing the efflux of chemo drugs out of the cells by P-Glycoprotein/ABCB1/MDR1. With this computational study, it is concluded that this compound might potentially reverse MDR, and hence can be taken forward for validation studies.Communicated by Ramaswamy H. Sarma.

Fast Photoswitchable Order-Disorder Transitions in Liquid-Crystalline Block Co-oligomers.

Optically driven ordering transitions are rarely observed in macromolecular systems, often because of kinetic limitations. Here, we report a series of block co-oligomers (BCOs) that rapidly order and disorder at room temperature in response to optical illumination, and the absence thereof. The system is a triblock where rigid azobenzene (Azo) mesogens are attached to each end of a flexible siloxane chain. UV-induced trans-to-cis Azo isomerization, and vice versa in the absence of UV light, drive disordering and ordering of lamellar superstructures and smectic mesophases, as manifested by liquefaction and solidification of the material, respectively. The impacts of chemical structure on BCO self-assembly and photoswitching kinetics are explored by in situ microscopy and X-ray measurements for different mesogen end groups (NO2 or CN), and different carbon chain lengths (0C or 12C) between the siloxane and the mesogen. The presence of the 12C spacer leads to hierarchical ordering with smectic layers of mesogens existing alongside larger length-scale lamellae, versus only smectic ordering without the spacer. These hierarchically ordered BCOs display highly persistent lamellar sheets that contrast with the tortuous, low-persistence "fingerprint"-type structures seen in conventional block copolymers. The reordering kinetics upon removal of UV illumination are extremely rapid (<5 s). This fast response is due to the electron-withdrawing NO2 and CN, which facilitate cis-to-trans isomerization via thermal relaxation at room temperature without additional stimuli. This work elucidates structure-property relationships in photoswitching BCOs and advances the possibility of developing systems in which ordered nanostructures can be easily optically written and erased.

Rhodamine-Installed Polynorbornenes: Molecular Design, Structure, and Stimuli-Responsive Properties.

The synthesis of a number of tailored architectures of rhodamine dye-norbornene conjugate monomers and corresponding homopolymers derived from them is described. The impact of the monomer architecture on the mechanochromic, photochromic, and thermochromic properties of rhodamine-modified polynorbornenes is reported. Color changes were caused by the reversible interconversion between the "open" and "closed" spirolactam form of the covalently attached dye. Monomers were synthesized in two principle architectures that varied on: (1) the number of polymerizable norbornene groups tethered to a bifunctional rhodamine dye; (2) the presence of flexible methylene spacers between the dye and the polymerizable norbornene groups. Introduction of norbornene groups on each of the two hydroxy groups of a bifunctional rhodamine resulted in a cross-linked polymer that exhibited better mechanochromic, photochromic, and thermochromic properties compared to the corresponding polymer without cross-links, derived from the derivatization of bifunctional rhodamine with only one norbornene. The introduction of flexible methylene spacers between the two polymerizable norbornenes and the dye molecule resulted in a polymeric framework with rapidly reversible color-changing properties upon mechanical or photostimulation. The ideal monomer molecular structure, whereby (1) attaching norbornene on both sides of the rhodamine dye and (2) methylene spacers between the dye and norbornenes on both sides afforded the nonpareil polymer structure that was capable of thermoreversible mechanochromic and photochromic features, and irreversible thermochromic features. These new materials may find utility as multi-stimuli-responsive soft materials.

Predictors of Functional Outcome in Unstable Ankle Fractures Treated Surgically - A Prospective Cohort Study.

INTRODUCTION: Unstable ankle injuries require anatomical reduction and stabilisation for optimal outcome. In spite of adequate care, a few patients have poor outcome. In this study, we assessed the risk factors that predict the clinical outcomes in surgically treated unstable ankle fractures. MATERIAL AND METHODS: This prospective cohort study was conducted on 68 patients who underwent surgical management for an unstable ankle injury. Demographic details, fracture type and associated medical comorbidities were recorded. Pre-operative radiographic assessment was done for all patients. At the end of one year follow-up, clinical (American Orthopaedic foot and ankle society-AOFAS and Olerud-Molander ankle - OMAS) scores and radiological parameters were assessed and analysed. RESULTS: Fracture dislocation (0.008), diabetes mellitus (0.017), level of alchohol consumption (0.008) and pre-operative talocrural angle (TCA) > 100° (0.03) were significant predictors of poor outcomes as per AOFAS. Fracture dislocation (0.029), diabetes mellitus (0.004), pre-operative TCA > 100° (0.009), female gender (0.001), age more than 60 years (0.002) and open injuries (0.034) had significantly poor outcome as per OMAS. Other parameters (smoking, hypertension, classification, syndesmotic injury, medial clear space and tibiofibular overlap) did not affect the outcome significantly. CONCLUSION: Our study showed that poor outcome predictors in unstable ankle fractures are age >60 years, female gender, diabetes mellitus, alcohol consumption, fracture dislocation, open fractures and pre-op TCA >100°.

Stabilization and X-ray Attenuation of PEGylated Cholesterol/Polycaprolactone-Based Perfluorooctyl Bromide Nanocapsules for CT Imaging.

Contrast-enhanced X-ray computed tomography plays an important role in cancer imaging and disease progression monitoring. Imaging using radiopaque nanoparticle platforms can provide insights on the likelihood of nanoparticle accumulation and can enable image-guided therapies. Perfluorooctyl bromide (PFOB)-loaded nanocapsules designed for this purpose were stabilized using an in-house synthesized PEGylated polycaprolactone-based copolymer (PEG-b-PCL(Ch)) and compared with commercial polycaprolactone employing a Quality-by-Design approach. PFOB is a dense liquid, weakly polarizable, and immiscible in organic and aqueous solvents; thus, carefully designed formulations for optimal colloidal stabilization to overcome settling-associated instability are required. PFOB-loaded nanocapsules exhibited high PFOB loading due to the intrinsic properties of PEG-b-PCL(Ch). Settling and caking are major sources of instability for PFOB formulations. However, the PEG-b-PCL(Ch) copolymer conferred the nanocapsules enough steric impediment and polymer shell elasticity to settle without significant caking, increasing the overall colloidal stability of the formulation. Furthermore, a clear relationship between nanocapsule physical properties and X-ray attenuation was established. Nanocapsules were able to enhance the X-ray contrast in vitro as a function of PFOB loading. This nanocapsule-based platform is promising for future translational studies and image-guided tumor therapy due to its enhanced contrastability and optimal colloidal stability.

Acetalization of glycerol and benzaldehyde to synthesize biofuel additives using SO4 2-/CeO2-ZrO2 catalyst.

Synthesis of 1,3- dioxane and 1,3-dioxolane, using sulfated CeO2-ZrO2 catalyst for acetalization of glycerol with benzaldehyde, is the focus of present work. SO4 2-/CeO2-ZrO2 catalyst was synthesized using combustion method. Experiments were carried out to analyze the effect of various solvents (n-hexane, toluene, tert-butyl alcohol, pentanol), molar ratios (1:3, 1:5, 1:7), catalyst loadings (3 wt%, 5 wt%, 9 wt %) and temperatures (80 °C, 90 °C, 100 °C) on glycerol conversion and selectivity of the products. Selectivity of 87.20% dioxolane and 12.80% dioxane was obtained at molar ratio of 1:3, 9 wt% catalyst loading and temperature of 100 °C.Strong NH3 desorption peak from NH3-TPD study indicated the high acidic strength of sulphated catalyst. Strong surface acidity and surface porosity (observed from TEM and SEM analysis) contributed to an enhanced activity of the catalyst for glycerol acetalization reaction. The kinetics of the reaction was studied using an elementary kinetic law. A correlation coefficient of 0.98 from the selected kinetic model proved that the rate of acetalization reaction was dependent on glycerol concentration and acetal formation was instantaneous. The study demonstrated the application of an environmentally benign, inexpensive, thermally stable, active SO4 2-/CeO2-ZrO2 catalyst for glycerol acetalization reaction to synthesize 1,3-dioxolane as the desired product.

Cholesteric mesophase based 1D photonic materials from self-assembly of liquid crystalline block and random terpolymers containing chromonic molecules.

We describe the influence of competing self-organizing phenomena on the formation of cholesteric mesophase in liquid crystalline brush block terpolymers (LCBBTs) and liquid crystalline random brush terpolymers (LCRBTs) containing chromonic molecules. A library of LCBBTs and LCRBTs are synthesized using ring-opening metathesis polymerization (ROMP) of norbornene side-chain functionalized monomers comprising cholesteryl mesogen (NBCh9), chromonic xanthenone (NBXan), and poly(ethylene glycol) (NBMPEG). Compression molded films of LCRBTs containing chromonic molecules display multilevel hierarchical structure in which cholesteric mesophase co-exists with π-π stacking of the chromonic mesophase along with PEG microphase segregated domains. This is unexpected as conventional LCBCPs and LCBBCs that lack chromonic molecules do not form cholesteric mesophases. The presence of π-π interactions modifies the interface at the IMDS so that both chromonic and cholesteric mesophases coexist leading to the manifestation of cholesteric phase for the first time within block architecture and is very reminiscent of previously published LCRBCs without chromonic molecules. The key to the observed hierarchical assembly in these LCBBTs containing chromonic molecules lies in the interplay of LC order, chromonic π-π stacking, PEG side chain microphase segregation, and their supramolecular cooperative motion. This unique "single component" polymer scaffold transforms our capacity to attain nanoscale hierarchies and optical properties from block architecture similar to nanoscale mesophases resulting in random architecture.

Predictors of Functional Outcome in Unstable Ankle Fractures Treated Surgically – A Prospective Cohort Study

@#Introduction: Unstable ankle injuries require anatomical reduction and stabilisation for optimal outcome. In spite of adequate care, a few patients have poor outcome. In this study, we assessed the risk factors that predict the clinical outcomes in surgically treated unstable ankle fractures. Material and methods: This prospective cohort study was conducted on 68 patients who underwent surgical management for an unstable ankle injury. Demographic details, fracture type and associated medical comorbidities were recorded. Pre-operative radiographic assessment was done for all patients. At the end of one year follow-up, clinical (American Orthopaedic foot and ankle societyAOFAS and Olerud-Molander ankle - OMAS) scores and radiological parameters were assessed and analysed. Results: Fracture dislocation (0.008), diabetes mellitus (0.017), level of alchohol consumption (0.008) and preoperative talocrural angle (TCA) > 100° (0.03) were significant predictors of poor outcomes as per AOFAS. Fracture dislocation (0.029), diabetes mellitus (0.004), preoperative TCA > 100° (0.009), female gender (0.001), age more than 60 years (0.002) and open injuries (0.034) had significantly poor outcome as per OMAS. Other parameters (smoking, hypertension, classification, syndesmotic injury, medial clear space and tibiofibular overlap) did not affect the outcome significantly. Conclusion: Our study showed that poor outcome predictors in unstable ankle fractures are age >60 years, female gender, diabetes mellitus, alcohol consumption, fracture dislocation, open fractures and pre-op TCA >100°.

Quantification of biomaterial dispersion during otologic procedures and role of barrier drapes in Covid 2019 era - a laboratory model.

BACKGROUND: Aerosol generation during temporal bone surgery caries the risk of viral transmission. Steps to mitigate this problem are of particular importance during the coronavirus disease 2019 pandemic. OBJECTIVE: To quantify the effect of barrier draping on particulate material dispersion during temporal bone surgery. METHODS: The study involved a cadaveric model in a simulated operating theatre environment. Particle density and particle count for particles sized 1-10 µ were measured in a simulated operating theatre environment while drilling on a cadaveric temporal bone. The effect of barrier draping to decrease dispersion was recorded and analysed. RESULTS: Barrier draping decreased counts of particles smaller than 5 µ by a factor of 80 in the operating theatre environment. Both particle density and particle count showed a statistically significant reduction with barrier draping (p = 0.027). CONCLUSION: Simple barrier drapes were effective in decreasing particle density and particle count in the operating theatre model and can prevent infection in operating theatre personnel.

Overcoming Wnt-ß-catenin dependent anticancer therapy resistance in leukaemia stem cells.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-ß-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate ß-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-ß-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated ß-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, ß-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated ß-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

Efficacy of Low-Frequency Repetitive Transcranial Magnetic Stimulation in Ischemic Stroke: A Double-Blind Randomized Controlled Trial.

OBJECTIVE: To investigate the role of low-frequency repetitive transcranial magnetic stimulation (rTMS) along with conventional physiotherapy in the functional recovery of patients with subacute ischemic stroke. DESIGN: Double-blind, parallel group, randomized controlled trial. SETTING: The outpatient department of a tertiary hospital participants: first ever ischemic stroke patients (N=96) in the previous 15 days were recruited and were randomized after a run-in period of 75±7 days into real rTMS (n=47) and sham rTMS (n=49) groups. INTERVENTION: Conventional physical therapy was given to both the groups for 90±7 days postrecruitment. Total 10 sessions of low-frequency rTMS on contralesional premotor cortex was administered to real rTMS group (n=47) over a period of 2 weeks followed by physiotherapy regime for 45-50 minutes. MAIN OUTCOME MEASURES: The primary efficacy outcomes were change in modified Barthel Index (mBI) score (pre- to postscore) and proportion of participants with mBI score more than 90, measured at 90±7 days postrecruitment. The secondary outcomes were change in Fugl-Meyer Assessment-upper extremity, Fugl-Meyer Assessment-lower extremity, Hamilton Depression Scale, modified Rankin Scale, and National Institute of Health and Stroke Scale (pre- to post-rTMS) scores at 90±7 days post recruitment. RESULTS: Modified intention to treat analysis showed a significant increase in the mBI score from pre- to post-rTMS in real rTMS group (4.96±4.06) versus sham rTMS group (2.65±3.25). There was no significant difference in proportion of patients with mBI>90 (55% vs 59%; P=.86) at 3 months between the groups. CONCLUSION: In patients with subacute ischemic stroke, 1-Hz low-frequency rTMS on contralesional premotor cortex along with conventional physical therapy resulted in significant change in mBI score.

Influence of the method of preparation on the characteristics and performance of cholesterol-based polymeric nanoparticles for redox-triggered release of doxorubicin in tumor cells.

Immature manufacturing and sub-optimal control of quality attributes hinder the effective translation of nanoformulations for cancer treatment, being partially responsible for the scarce number of products on the market. The effect of the method of preparation on the performance of complex formulations such as bio-responsive nanomedicines needs further understanding. In this study, we investigated the the influence of the method of preparation on the characteristics and bio-responsiveness of doxorubicin-loaded redox-sensitive nanoparticles (DOX-SS-NPs), formed by a biocompatible cholesterol-based amphiphilic block copolymer (PC5MA-SS-PEO). Two commonly used preparation techniques: (1) cosolvent removal and (2) an O/W emulsion method were compared and the in vitro and in vivo performance of promising formulations was assessed. Besides particle size distribution and drug loading, the response of the nanoparticles to reducing environments and subsequent release kinetics and cytotoxicity were also affected by the method of preparation. The investigation and understanding of this extensive influence, led to a DOX-SS-NPs formulation with significant in vivo efficacy and an improved safety profile when evaluated against free doxorubicin (DOX-HCl) and the commercial pegylated liposomal form (Doxil®). Our findings highlight the importance of formulation optimization and support the use of systematic approaches like Quality by Design to the development of bio-responsive nanomedicines for cancer treatment.

Kinetic and equilibrium modeling of biosorption of nickel (II) and cadmium (II) on brewery sludge.

In the current study, utilization of industrial waste brewery sludge for the biosorption of nickel (II) and cadmium (II) has been explored. The suitable conditions for the effective removal of Ni (II) and Cd (II) from aqueous solutions were examined. The kinetic evaluation showed that the biosorption process using the sludge followed pseudo-second order kinetics. In the presence of a metal co-ion, competitive and preferential biosorption was observed. The Langmuir model and Freundlich model were able to describe the sorption equilibrium for biosorption of Ni (II) and Cd (II) ions in single and dual metal systems. The effects of co-ion concentrations onto mono-component isotherm parameters (Langmuir and Freundlich) were studied and the inhibitory effect of co-ion concentration was observed. The effective reusability of biomass was assessed by three cycles of sorption-desorption. The sludge, owing to its high biosorption intensity and large availability from the local supply, is a better biosorbent for the treatment of Ni (II) and Cd (II) contaminated water.