Clinical and radiographic evaluation of demineralized freeze-dried bone allograft with concentrated growth factor versus concentrated growth factor alone in the treatment of intrabony defects.

BACKGROUND: Periodontal disease is one of the major causes of alveolar bone loss. There are various ways of regenerating the lost bone, i.e. guided tissue regeneration, bone grafts, and growth factors. In this purview, it becomes immensely important for a clinician to decide the best modality of treatment. In this study, we compared the effect of demineralized freeze-dried bone allograft (DFDBA) in combination with concentrated growth factors (CGF) verses CGF alone. METHODS: This double-blind, split-mouth study was conducted on ten patients with two comparable bilateral intrabony defects. Each pair of defects was randomly treated by DFDBA + CGF or CGF alone. Clinical parameters such as plaque index (PI), modified gingival index (MGI), pocket probing depth (PPD), and relative attachment level (RAL) were recorded at baseline, three months, and six months. In addition, radiograph with grids was also taken at baseline and six months. The paired t-test was used to compare the pre- and post-treatment values and the unpaired t-test was used to compare the test and control group. RESULTS: The PI score decreased significantly from baseline to six months. Similarly, the mean MGI score decreased significantly from baseline to six months. The intragroup comparison showed that there was a significant reduction in PPD in both the test and control group. However, the intergroup comparison showed that the reduced pocket depth was not significant. The intragroup radiographic comparison showed that there was the significant formation of bone in both the test and control group but inter-group showed that the formation of bone among both the group were non-significant. CONCLUSION: Radiographic and clinical outcomes of this study concluded that post six months, both groups demonstrated significant improvement in clinical and radiographic parameters. However, the addition of DFDBA to CGFs did not give any additional benefits.

Chromatin Remodeling in the Brain-a NuRDevelopmental Odyssey.

During brain development, the genome must be repeatedly reconfigured in order to facilitate neuronal and glial differentiation. A host of chromatin remodeling complexes facilitates this process. At the genetic level, the non-redundancy of these complexes suggests that neurodevelopment may require a lexicon of remodelers with different specificities and activities. Here, we focus on the nucleosome remodeling and deacetylase (NuRD) complex. We review NuRD biochemistry, genetics, and functions in neural progenitors and neurons.

FDA Approval Summary: Atezolizumab and Durvalumab in Combination with Platinum-Based Chemotherapy in Extensive Stage Small Cell Lung Cancer.

The U.S. Food and Drug Administration (FDA) granted approval to atezolizumab and durvalumab in March of 2019 and 2020, respectively, for use in combination with chemotherapy for first-line treatment of patients with extensive stage small cell lung cancer. These approvals were based on data from two randomized controlled trials, IMpower133 (atezolizumab) and CASPIAN (durvalumab). Both trials demonstrated an improvement in overall survival (OS) with anti-programmed death ligand 1 antibodies when added to platinum-based chemotherapy as compared with chemotherapy alone. In IMpower133, patients receiving atezolizumab with etoposide and carboplatin demonstrated improved OS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.54-0.91; p = .0069), with median OS of 12.3 months compared with 10.3 months in patients receiving etoposide and carboplatin. In CASPIAN, patients receiving durvalumab with etoposide and either cisplatin or carboplatin also demonstrated improved OS (HR, 0.73; 95% CI, 0.59-0.91; p = .0047) with median OS of 13.0 months compared with 10.3 months in patients receiving etoposide and either cisplatin or carboplatin. The safety profiles of both drugs were generally consistent with known toxicities of immune-checkpoint inhibitor therapies. This review summarizes the FDA perspective and data supporting the approval of these two agents. IMPLICATIONS FOR PRACTICE: Effective therapeutic options for small cell lung cancer (SCLC) are limited, and there has been modest improvement in the overall survival (OS) of patients with SCLC over the past 3 decades. The approvals of atezolizumab and of durvalumab in combination with chemotherapy for first-line treatment of patients with extensive stage SCLC represent the first approved therapies with OS benefit for this patient population since the approval of etoposide in combination with other approved chemotherapeutic agents. Additionally, the efficacy results from IMpower133 and CASPIAN lay the groundwork for possible further evaluation in other treatment settings in this disease.

A Casz1-NuRD complex regulates temporal identity transitions in neural progenitors.

Neural progenitor cells undergo identity transitions during development to ensure the generation different types of neurons and glia in the correct sequence and proportions. A number of temporal identity factors that control these transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how Casz1, the mammalian orthologue of Drosophila castor, regulates competence during retinal development. We show that Casz1 is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As additional temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through this common biochemical process to regulate neurogenesis.

Application of robotic technologies in lower gastrointestinal tract endoscopy: A systematic review.

BACKGROUND: Conventional optical colonoscopy is considered the gold standard investigation for colorectal tract pathology including colorectal malignancy, polyps and inflammatory bowel disease. Inherent limitations exist with current generation endoscopic technologies, including, but not limited to, patient discomfort, endoscopist fatigue, narrow field of view and missed pathology behind colonic folds. Rapid developments in medical robotics have led to the emergence of a variety of next-generation robotically-augmented technologies that could overcome these limitations. AIM: To provide a comprehensive summary of recent developments in the application of robotics in lower gastrointestinal tract endoscopy. METHODS: A systematic review of the literature was performed from January 1, 2000 to the January 7, 2021 using EMBASE, MEDLINE and Cochrane databases. Studies reporting data on the use of robotic technology in ex vivo or in vivo animal and human experiments were included. In vitro studies (studies using synthetic colon models), studies evaluating non-robotic technology, robotic technology aimed at the upper gastrointestinal tract or paediatric endoscopy were excluded. System ergonomics, safety, visualisation, and diagnostic/therapeutic capabilities were assessed. RESULTS: Initial literature searching identified 814 potentially eligible studies, from which 37 were deemed suitable for inclusion. Included studies were classified according to the actuation modality of the robotic device(s) as electromechanical (EM) (n = 13), pneumatic (n = 11), hydraulic (n = 1), magnetic (n = 10) and hybrid (n = 2) mechanisms. Five devices have been approved by the Food and Drug Administration, however most of the technologies reviewed remain in the early phases of testing and development. Level 1 evidence is lacking at present, but early reports suggest that these technologies may be associated with improved pain and safety. The reviewed devices appear to be ergonomically capable and efficient though to date no reports have convincingly shown diagnostic or therapeutic superiority over conventional colonoscopy. CONCLUSION: Significant progress in robotic colonoscopy has been made over the last couple of decades. Improvements in design together with the integration of semi-autonomous and autonomous systems over the next decade will potentially result in robotic colonoscopy becoming more commonplace.

Treating Public Health Dilemma of Gingival Recession by the Dehydrated Amnion Allograft: A 5-Year Longitudinal Study.

Aim: This study aimed to evaluate the efficacy of dehydrated amnion allograft with coronally positioned flap procedure in paired Miller's class I recession defects. Methods: A total of 51 subjects were included in the study with bilateral Miller's class I gingival recession defects. In the test group, patients were treated with an amniotic membrane (AM) with a coronally positioned flap, while in the control group, patients were treated with coronally positioned flap alone. Clinical parameters such as recession depth, recession width (RW), probing depth (PD), relative attachment level (RAL), width of keratinized gingiva (WKG), and thickness of keratinized gingiva (TKG) were recorded at baseline and after 5 years of follow-up. Result: The mean baseline recession was 2.95 ± 0.89 in the test group and 2.70 ± 0.85 in the control group, and both were statically non-significant. At the end of 6 months, all the parameters, when compared with the baseline, showed a significant improvement. Intergroup comparison showed the non-significant difference in all settings except the TKG. Conclusion: AM proved to help improve the TKG. This increase in thickness helps in the long-term maintenance of the gingival margin in Miller's class I recession defect.

Socioeconomic and cultural impact of tobacco in India.

Tobacco consumed either in the form of smoke or smokeless is hazardous to the human body. Death toll due to tobacco globally, has risen to about 6.4 million annually, and is on a constant increase. Since long, tobacco consumption has been attributed to a variety of factors including geographical variation, cultural factors and other associated variables. Earlier tobacco was considered as a taboo, but with advent of 21st century and commercialization of tobacco it has been prevalent among males and females. Global adult tobacco survey (GATS) in India 2016-17 revealed that there has been drop of 34.1% tobacco consumers in India, mainly due to the increasing awareness and anti-tobacco campaigns and tobacco hazards warning on the packs. Analysing the changes in trends by healthcare professionals can prove to be a valuable tool in devising strategies to control and limit the morbidity and mortality caused due to tobacco consumption.

Nrf2 Transcription Factor Can Directly Regulate mTOR: LINKING CYTOPROTECTIVE GENE EXPRESSION TO A MAJOR METABOLIC REGULATOR THAT GENERATES REDOX ACTIVITY.

Nrf2 is a master transcription factor that regulates a wide variety of cellular proteins by recognizing and binding to antioxidant response elements (AREs) in their gene promoter regions. In this study we show that increasing cellular Nrf2 results in transcriptional activation of the gene for mTOR, which is central to the PI3K signaling pathway. This is the case in cells with normal physiological PI3K. However, in cells with abnormally active PI3K increased cellular Nrf2 levels have no effect on mTOR. ChIP assays results show that increased Nrf2 binding is associated with decreased p65 binding and H3-K27me3 signal (marker of gene repression) as well as increased H3-K4me3 signal (marker of gene activation). However, in cells with PI3K activation, no effect of cellular Nrf2 increase on mTOR transcription was observed. In these cells, increasing Nrf2 levels increases Nrf2 promoter binding marginally, whereas p65 binding and H3-K27me3 mark were significantly increased, and H3-K4me3 signal is reduced. Together, these data show for the first time that Nrf2 directly regulates mTOR transcription when the PI3K pathway is intact, whereas this function is lost when PI3K is activated. We have identified a link between the Nrf2 system of sensing environmental stress and mTOR, which is a key cellular protein in metabolism. Studies in cells with activating mutations in the PI3K pathway suggest that Nrf2 transcriptional regulation of mTOR is related to promoter binding of p65 and of methylation of histone residues permissive of transcription.

Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.

Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal-recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.

Predictors of Treatment Decisions in Multidisciplinary Oncology Meetings: A Quantitative Observational Study.

BACKGROUND: In many healthcare systems, treatment recommendations for cancer patients are formulated by multidisciplinary tumor boards (MTBs). Evidence suggests that interdisciplinary contributions to case reviews in the meetings are unequal and information-sharing suboptimal, with biomedical information dominating over information on patient comorbidities and psychosocial factors. This study aimed to evaluate how different elements of the decision process affect the teams' ability to reach a decision on first case review. METHODS: This was an observational quantitative assessment of 1045 case reviews from 2010 to 2014 in cancer MTBs using a validated tool, the Metric for the Observation of Decision-making. This tool allows evaluation of the quality of information presentation (case history, radiological, pathological, and psychosocial information, comorbidities, and patient views), and contribution to discussion by individual core specialties (surgeons, oncologists, radiologists, pathologists, and specialist cancer nurses). The teams' ability to reach a decision was a dichotomous outcome variable (yes/no). RESULTS: Using multiple logistic regression analysis, the significant positive predictors of the teams' ability to reach a decision were patient psychosocial information (odds ratio [OR] 1.35) and the inputs of surgeons (OR 1.62), radiologists (OR 1.48), pathologists (OR 1.23), and oncologists (OR 1.13). The significant negative predictors were patient comorbidity information (OR 0.83) and nursing inputs (OR 0.87). CONCLUSIONS: Multidisciplinary inputs into case reviews and patient psychosocial information stimulate decision making, thereby reinforcing the role of MTBs in cancer care in processing such information. Information on patients' comorbidities, as well as nursing inputs, make decision making harder, possibly indicating that a case is complex and requires more detailed review. Research should further define case complexity and determine ways to better integrate patient psychosocial information into decision making.

The anatomy of clinical decision-making in multidisciplinary cancer meetings: A cross-sectional observational study of teams in a natural context.

In the UK, treatment recommendations for patients with cancer are routinely made by multidisciplinary teams in weekly meetings. However, their performance is variable.The aim of this study was to explore the underlying structure of multidisciplinary decision-making process, and examine how it relates to team ability to reach a decision.This is a cross-sectional observational study consisting of 1045 patient reviews across 4 multidisciplinary cancer teams from teaching and community hospitals in London, UK, from 2010 to 2014. Meetings were chaired by surgeons.We used a validated observational instrument (Metric for the Observation of Decision-making in Cancer Multidisciplinary Meetings) consisting of 13 items to assess the decision-making process of each patient discussion. Rated on a 5-point scale, the items measured quality of presented patient information, and contributions to review by individual disciplines. A dichotomous outcome (yes/no) measured team ability to reach a decision. Ratings were submitted to Exploratory Factor Analysis and regression analysis.The exploratory factor analysis produced 4 factors, labeled "Holistic and Clinical inputs" (patient views, psychosocial aspects, patient history, comorbidities, oncologists', nurses', and surgeons' inputs), "Radiology" (radiology results, radiologists' inputs), "Pathology" (pathology results, pathologists' inputs), and "Meeting Management" (meeting chairs' and coordinators' inputs). A negative cross-loading was observed from surgeons' input on the fourth factor with a follow-up analysis showing negative correlation (r = -0.19, P < 0.001). In logistic regression, all 4 factors predicted team ability to reach a decision (P < 0.001).Hawthorne effect is the main limitation of the study.The decision-making process in cancer meetings is driven by 4 underlying factors representing the complete patient profile and contributions to case review by all core disciplines. Evidence of dual-task interference was observed in relation to the meeting chairs' input and their corresponding surgical input into case reviews.

Pools of programmed death-ligand within the oral cavity tumor microenvironment: Variable alteration by targeted therapies.

BACKGROUND: Enhanced understanding of programmed death-ligand (PD-L) expression in oral cancer is important for establishing rational combinations of emerging immune checkpoint and molecular targeted therapies. METHODS: We assessed PD-L and interferon (IFN) expression in immunogenic murine oral cancer-1 (MOC1) and poorly immunogenic MOC2 cell models after treatment with mammalian target of rapamycin (mTOR) and MEK1/2 small molecule inhibitors in vitro and in vivo. RESULTS: PD-L1 but not PD-L2 is expressed on MOC1 and 2 cells and is type I and II IFN-dependent. PD-L1 is differentially expressed on cancer and endothelial cells and infiltrating myeloid-derived suppressor cells, macrophages, and regulatory T cells (Tregs) in highly and poorly immunogenic tumors. PD-L1 expression is variably altered after treatment with inhibitors in vivo, with an imperfect relationship to alterations in IFN levels in the tumor microenvironment. CONCLUSION: PD-L1 expressed on cancer and infiltrating immune cells is variably altered by targeted therapies and may, in part, reflect changes in tumor IFN. © 2016 Wiley Periodicals, Inc. Head Neck 38:1176-1186, 2016.

Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir.

Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7 ± 2.0%, 41.8 ± 1.9%, and 45.3 ± 2.2%; drug loadings 3.87 ± 0.20%, 2.79 ± 0.13% and 3.02 ± 0.15%; yield 85.2 ± 3.0%, 86.9 ± 4.6% and 76.9 ± 2.1%; particle sizes 116.6 ± 4.5, 143.0 ± 3.8 and 134.1 ± 5.2 nm; and zeta potential -15.0 ± 4.96, -13.8 ± 5.26 and -13.9 ± 5.14 mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.

Uptake and bioconversion of stereoisomeric dipeptide prodrugs of ganciclovir by nanoparticulate carriers in corneal epithelial cells.

PURPOSE: The objective of this study is to investigate cellular uptake of prodrug-loaded nanoparticle (NP). Another objective is to study bioconversion of stereoisomeric dipeptide prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and d-Val-l-Val-GCV (DLGCV) in human corneal epithelial cell (HCEC) model. METHODS: Poly(D,L-lactic-co-glycolic acid) (PLGA) NP encapsulating prodrugs of GCV were formulated under a double emulsion method. Fluorescein isothiocyanate isomer-PLGA conjugates were synthesized to fabricate biocompatible fluorescent PLGA NP. Intracellular uptake of FITC-labeled NP was visualized by a fluorescent microscope in HCEC cells. RESULTS: Fluorescent PLGA NP and non-fluorescent NP display similar hydrodynamic diameter in the range of 115-145 nm with a narrow particle size distribution and zeta potentials around -13 mV. Both NP types showed identical intracellular accumulation in HCEC cells. Maximum uptake (around 60%) was noted at 3 h for NP. Cellular uptake and intracellular accumulation of prodrugs are significantly different among three stereoisomeric dipeptide prodrugs. The microscopic images show that NPs are avidly internalized by HCEC cells and distributed throughout the cytoplasm instead of being localized on the cell surface. Following cellular uptake, prodrugs released from NP gradually bioreversed into parent drug GCV. LLGCV showed the highest degradation rate, followed by LDGCV and DLGCV. CONCLUSION: LLGCV, LDGCV and DLGCV released from NP exhibited superior uptake and bioreversion in corneal cells.

mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer.

We investigated the effects of mTOR and MEK1/2 inhibition on tumor growth and the tumor microenvironment in immunogenic and poorly immunogenic models of murine oral cancer. In vitro, rapamycin and PD901 inhibited signaling through expected downstream targets, but only PD901 reduced viability and altered function of MOC cells. Following transplantation of MOC cells into immune-competent mice, effects on both cancer and infiltrating immune cells were characterized following rapamycin and/or PD901 treatment for 21 days. In vivo, both rapamycin and PD901 inhibition reduced primary growth of established MOC tumors on treatment. Following withdrawal of PD901, rapid rebound of tumor growth limited survival, whereas durable tumor control was observed following rapamycin treatment in immunogenic MOC1 tumors despite more robust inhibition of oncogenic signaling by PD901. Characterization of the immune microenvironment revealed diminished infiltration and activation of antigen-specific CD8+ T-cells and other immune cells following PD901 but not rapamycin in immunogenic tumors. Subsequent in vitro T-cell assays validated robust inhibition of T-cell expansion and activation following MEK inhibition compared to mTOR inhibition. CD8 cell depletion abrogated rapamycin-induced primary tumor growth inhibition in MOC1 mice. These data have critical implications in the design of combination targeted and immune therapies in oral cancer.

Novel delivery approaches for cancer therapeutics.

Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer.

MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma.

PURPOSE: Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined. EXPERIMENTAL DESIGN: We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901). RESULTS: PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo. CONCLUSIONS: PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo.

Episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery - recent research advances and patents.

Subconjunctival/episcleral, intrascleral, and suprachoroidal routes of drug delivery for treatment of posterior segment eye diseases have become more feasible and popular in the past few years. These routes have the advantage of bypassing the main barriers to topical drug penetration, the ocular surface epithelium, the conjunctivallymphatics, and in the case of deep intrascleral and suprachoroidial delivery, the sclera barrier. Many ocular drug delivery application devices, drug delivery methods, and therapeutics that have been developed for intravitreal use can also be used subconjunctivally, intrasclerally, and in the suprachoroidal space. Alternatively, site-specific devices, such microneedles, and therapeutics, such as hydrogel matrices, have been developed to enhance ocular drug delivery. This manuscript will review the recent research advances and patents on episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery.

Cancer patients' perspectives on multidisciplinary team working: an exploratory focus group study.

This qualitative, focus-group study explores what patients understand about the multidisciplinary team (MDT) in cancer care. Participants were positive towards MDT working, and by strengthening the role of nurses in MDT decision-making, the representation of patients' interests can be improved.

Molecular expression and functional activity of sodium dependent multivitamin transporter in human prostate cancer cells.

Nutrient transporters expressed on cell membrane have been targeted for enhancing bioavailability of poorly permeable drugs. Sodium dependent multivitamin transporter (SMVT) is once such carrier system, utilized for improving drug targeting to specific tissues. Therefore, the main objective of this study is to characterize SMVT in human derived prostate cancer cells (PC-3). Reverse transcription polymerase chain reaction (RT-PCR) analysis has provided product band at 774 bp, specific to SMVT. The mechanism and intracellular regulation of [3H]-biotin is also studied. [3H]-biotin uptake is found to be time and concentration dependent with K(m) and V(max) values of 19±2 µM and 23±1 pmol/min/mg protein, respectively. The uptake process is saturable in micromolar concentration range but linear in nanomolar concentration range. [3H]-biotin uptake shows significant sodium, temperature, pH and energy dependency. The process is strongly inhibited by unlabeled biotin and structural analogs such as desthiobiotin, pantothenate, lipoate and valeric acid. Intracellular regulatory pathways such as Ca(2+)/calmodulin and PKC pathway but not PTK pathway appears to play an important role in modulating [3H]-biotin uptake. This study for the first time confirms the molecular expression of SMVT and demonstrates that SMVT, responsible for biotin uptake is functionally active in PC-3 cells.