Search

The use of plastic waste as a partial or complete replacement for coarse aggregate in concrete mixtures has been studied in recent years. However, the quality and quantity of coarse plastic waste particles have been a challenge. This study aims to investigate the mechanical performance of concrete with Bakelite plastic waste as a partial replacement for coarse aggregate. Six different concrete mixtures with various Bakelite dosages, ranging from 0 % to 10 %, were tested. The results indicate that the addition of Bakelite plastic alters the behaviour of the concrete and reduces compressive and flexural strengths at lower dosages. The inclusion of Bakelite waste in concrete mixtures generally leads to a decrease in compressive and split tensile strength, with the exception of the mixture containing 6 % Bakelite, which showed increased strength. Although there is a slight reduction in flexural strength, Bakelite waste prevents sudden specimen breakage and maintains specimen integrity. The ultimate load capacity of reinforced concrete beams with Bakelite waste is generally lower compared to the control beam, except for the 8 % waste Bakelite beam which demonstrated a similar ultimate load capacity of 60 kN. Although managing Bakelite waste can be difficult because it can lead to the creation of microplastics in landfills over time, utilizing Bakelite waste in concrete can be a sustainable method of waste management. The innovative use of Bakelite waste as a partial replacement for coarse aggregate in concrete offers a sustainable solution to the problem of waste management and addresses the environmental concerns related to the disposal of non-biodegradable plastics. This research provides a practical solution for developing eco-friendly and cost-effective construction materials while promoting sustainable waste management practices.

Here, Biswas et al. present and characterize a second-generation model of HBV infection in rhesus macaques, showing that extended infection requires suppression of host immunity.

Brian De,1,* Sweet Ping Ng,1,2,* Amy Y Liu,1 Santiago Avila,1 Randa Tao,3 Emma B Holliday,1 Zachary Brownlee,4 Ahmed Kaseb,5 Sunyoung Lee,3 Kanwal Raghav,5 Jean-Nicolas Vauthey,6 Bruce D Minsky,1 Joseph M Herman,1 Prajnan Das,1 Grace L Smith,1 Cullen M Taniguchi,1 Sunil Krishnan,7 Christopher H Crane,8 Clemens Grassberger,9 Theodore S Hong,9 Steven H Lin,1 Albert C Koong,1 Radhe Mohan,1 Eugene J Koay1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, Austin Health, Melbourne, Victoria, Australia; 3Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA; 4Department of Radiation Oncology, Tufts Medical Center, Boston, MA, USA; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA; 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Eugene J KoayMD Anderson Cancer Center, Department of Radiation Oncology, 1400 Pressler St. Unit 1422, Houston, TX, 77030, USATel + 1 713-563-2381Fax +1 713-563-2331Email EKoay@mdanderson.orgBackground: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.Results: Of 143 patients identified, the median age was 66 (range, 19– 90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13– 25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/μL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.Conclusion: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.Keywords: lymphocyte count, circulating lymphocytes, splenic dose, liver dose, overall survival

Abstract Background Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways, and adenosine triphosphate (ATP) levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor rocaglamide A (RocA) induces thioredoxin-interacting protein (TXNIP). TXNIP is a negative regulator of glucose uptake; thus, its induction by RocA links translation to the availability of glucose. MondoA is the principal regulator of glucose-induced transcription, and its activity is triggered by the glycolytic intermediate, glucose 6-phosphate (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial ATP (mtATP), suggesting a critical role in the cellular response to these energy sources. TXNIP expression is entirely dependent on MondoA; therefore, we investigated how protein synthesis inhibitors impact its transcriptional activity. Methods We investigated how translation regulates MondoA activity using cell line models and loss-of-function approaches. We examined how protein synthesis inhibitors effect gene expression and metabolism using RNA-sequencing and metabolomics, respectively. The biological impact of RocA was evaluated using cell lines and patient-derived xenograft organoid (PDxO) models. Results We discovered that multiple protein synthesis inhibitors, including RocA, increase TXNIP expression in a manner that depends on MondoA, a functional electron transport chain and mtATP synthesis. Furthermore, RocA and cycloheximide increase mtATP and G6P levels, respectively, and TXNIP induction depends on interactions between the voltage-dependent anion channel (VDAC) and hexokinase (HK), which generates G6P. RocA treatment impacts the regulation of ~ 1200 genes, and ~ 250 of those genes are MondoA-dependent. RocA treatment is cytotoxic to triple negative breast cancer (TNBC) cell lines and shows preferential cytotoxicity against estrogen receptor negative (ER−) PDxO breast cancer models. Finally, RocA-driven cytotoxicity is partially dependent on MondoA or TXNIP. Conclusions Our data suggest that protein synthesis inhibitors rewire metabolism, resulting in an increase in mtATP and G6P, the latter driving MondoA-dependent transcriptional activity. Further, MondoA is a critical component of the cellular transcriptional response to RocA. Our functional assays suggest that RocA or similar translation inhibitors may show efficacy against ER− breast tumors and that the levels of MondoA and TXNIP should be considered when exploring these potential treatment options.

Abstract Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)‐based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia‐preconditioned, allogeneic human MSCs combined with the beta‐adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 μM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 105 cells/cm2 on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7‐day treatment, accumulative steady‐state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro‐inflammatory cytokines IL‐1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti‐inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5‐fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.

Head injury is the major cause of death in young adult population worldwide with associated high morbidity. The objective of this study is to find out the outcome and factors affecting the outcome in isolated traumatic acute subdural hematoma. All patients with isolated acute subdural hematoma presenting within 24 hours of trauma and admitted over a period of 1 year were included in this study. Patient was classified according to Glasgow Coma Scale(GCS) after resuscitation in the emergency department. The outcome of the patient was recorded according to the Glasgow Outcome Scale at the time of discharge and at 3 months after the trauma in follow-up. Statistical analysis was performed to find the correlation between GCS, papillary changes and radiological finding in the form of midline shift and hematoma volume to dichotomized outcome. Out of 38 patients enrolled in the study, 33 patients had favorable outcome. Surgery was performed in 12 patients out of whom 4 patients had unfavorable outcome. GCS score, papillary changes, midline shift and hematoma volume were found to have significant association with the outcome in isolated traumatic acute subdural hematoma. Clinical parameters and radiological parameters can gauge the outcome in isolated traumatic brain injury.

Abstract We report on the tunable and enhanced dielectric properties of tungsten (W) incorporated gallium oxide (Ga2O3) polycrystalline electroceramics for energy and power electronic device applications. The W‐incorporated Ga2O3 (Ga2−2xWxO3, 0.00 ≤ x ≤ 0.20; GWO) compounds were synthesized by the high‐temperature solid‐state chemical reaction method by varying the W‐content. The fundamental aspects of the dielectric properties in correlation with the crystal structure, phase, and microstructure of the GWO polycrystalline compounds has been investigated in detail. A detailed study performed ascertains the W‐induced changes in the dielectric constant, loss tangent (tan δ) and ac conductivity. It was found that the dielectric constant increases with addition of W in the system as a function of temperature (25°C‐500°C). Frequency dependence (102‐106 Hz) of the dielectric constant follows the modified Debye model with a relaxation time of ∼20 to 90 μs and a spreading factor of 0.39 to 0.65. The dielectric constant of GWO is temperature independent almost until ∼300°C, and then increases rapidly in the range of 300°C to 500°C. W‐induced enhancement in the dielectric constant of GWO is fully evident in the frequency and temperature dependent dielectric studies. The frequency and temperature dependent tan δ reveals the typical behavior of relaxation loses in GWO. Small polaron hopping mechanism is evident in the frequency dependent electrical transport properties of GWO. The remarkable effect of W‐incorporation on the dielectric and electrical transport properties of Ga2O3 is explained by a two‐layer heterogeneous model consisting of thick grains separated by very thin grain boundaries along with the formation of a Ga2O3‐WO3 composite was able to account for the observed temperature and frequency dependent electrical properties in GWO. The results demonstrate that the structure, electrical and dielectric properties can be tailored by tuning W‐content in the GWO compounds.

Abstract Introduction Organizational transformations have focused on creating and fulfilling value for customers, leveraging advanced technologies. Transforming public health (PH) faces an interesting challenge. The value created (preventive practices) to fulfill policy makers’ desire to reduce healthcare costs is realized by several external partners with varying goals and is practiced by the public (value in use), which often places low priority on prevention. Methods This paper uses value lens to argue that PH transformation strategy must align the goals of all stakeholders involved. This may include allowing partners and the public to contextualize the preventive practices to see the value in near term and as relevant. It also means extending the number of partners PH uses and helping them connect with the public to seek shared alignment in shared goals of value fulfillment and value‐in‐use. Results Using lessons from Covid‐19 and PH experience with partners in four different sectors: business, healthcare, public and community, the paper illustrates how PH transformation strategy can be implemented going forward. Conclusions We conclude the paper with five distinct directions for future research to create and sustain value using the framework of learning health systems.

Buildings are constructed for accommodating living and industrial needs. Floor cleaning robots have been developed to cater to the demand of these buildings. Area coverage and coverage time are crucial performance factors of a floor cleaning robot. Reconfigurable tiling robots have been introduced over fixed shape robots to improve area coverage in floor cleaning applications compared to robots with fixed morphologies. However, area coverage and coverage time of a tiling robot compromised one another. This study proposes a novel concept that considers the ability of a tiling robot to configure both its morphology and size according to the environment. This concept is inspired by the pleomorphism that could be seen in bacteria. In this regard, P-hTetro, a pleomorphic tiling robot that can reconfigure its morphology and size, is considered. A novel coverage strategy for realizing the size reconfiguration is also proposed. According to this strategy, the robot covers obstacle-free areas with its maximum size, while an obstacle cluster is covered after shrinking to an optimum size. The optimum size for reconfiguration is determined by the genetic algorithm based on the arrangement of the environment. The performance and behavior of the proposed P-hTetro have been compared against that of an existing tiling robot which has a fixed size. According to the statistical outcomes, a tiling robot with the ability to reconfigure its size can significantly improve the performance in the aspects of area coverage and coverage time compared to a tiling robot with no ability to reconfigure its size.

Mutations of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, including ovarian cancer. Approximately half of ovarian clear cell carcinomas (OCCC) carry mutations in the SWI/SNF subunit ARID1A, while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) presents with inactivating mutations of the SWI/SNF ATPase SMARCA4 alongside epigenetic silencing of the ATPase SMARCA2. Loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may also interfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates the chromatin landscape and gene expression by demethylating proteins such as histone H3. Cross-cancer analysis of the TCGA database shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. SCCOHT and OCCC cell lines have shown sensitivity to the reversible LSD1 inhibitor SP-2577 (Seclidemstat), suggesting that SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Moreover, it has been shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of endogenous retroviral elements and may thereby overcome resistance to checkpoint blockade. In this study, we investigated the ability of SP-2577 to promote anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC cell lines. We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.

Abstract Background Mesenchymal stem cells (MSCs) represent an important source for cell therapy in regenerative medicine. MSCs have shown promising results for repair of damaged tissues in various degenerative diseases in animal models and also in human clinical trials. However, little is known about the factors that could enhance the migration and tissue-specific engraftment of exogenously infused MSCs for successful regenerative cell therapy. Previously, we have reported that interleukin-3 (IL-3) prevents bone and cartilage damage in animal models of rheumatoid arthritis and osteoarthritis. Also, IL-3 promotes the differentiation of human MSCs into functional osteoblasts and increases their in-vivo bone regenerative potential in immunocompromised mice. However, the role of IL-3 in migration of MSCs is not yet known. In the present study, we investigated the role of IL-3 in migration of human MSCs under both in-vitro and in-vivo conditions. Methods MSCs isolated from human bone marrow, adipose and gingival tissues were used for in-vitro cell migration, motility and wound healing assays in the presence or absence of IL-3. The effect of IL-3 preconditioning on expression of chemokine receptors and integrins was examined by flow cytometry and real-time PCR. The in-vivo migration of IL-3-preconditioned MSCs was investigated using a subcutaneous matrigel-releasing stromal cell-derived factor-1 alpha (SDF-1α) model in immunocompromised mice. Results We observed that human MSCs isolated from all three sources express IL-3 receptor-α (IL-3Rα) both at gene and protein levels. IL-3 significantly enhances in-vitro migration, motility and wound healing abilities of MSCs. Moreover, IL-3 preconditioning upregulates expression of chemokine (C-X-C motif) receptor 4 (CXCR4) on MSCs, which leads to increased migration of cells towards SDF-1α. Furthermore, CXCR4 antagonist AMD3100 decreases the migration of IL-3-treated MSCs towards SDF-1α. Importantly, IL-3 also induces in-vivo migration of MSCs towards subcutaneously implanted matrigel-releasing-SDF-1α in immunocompromised mice. Conclusions The present study demonstrates for the first time that IL-3 has an important role in enhancing the migration of human MSCs through regulation of the CXCR4/SDF-1α axis. These findings suggest a potential role of IL-3 in improving the efficacy of MSCs in regenerative cell therapy.

Abstract Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR 19del , but not the EGFR L858R . In the current study we use modelling and simulations to show that structural constraints in EGFR 19del deletion result in significantly attenuated flexibilities in the binding pocket resulting in strong hydrogen and halogen bonds with afatinib in the EGFR 19del ; these constraints are modulated by buried water and result in the differential affinities of afatinib for the different mutants. SNP analysis of residues surrounding the buried water points to the likelihood of further differential effects of afatinib and provides a compelling case for investigating the effects of the SNPs towards further stratification of patients for ensuring the most effective use of afatinib.

Introduction: Neural tube defects are among the most common congenital malformations and a major cause of health problems in surviving children, especially in developing countries. Although the incidence of spinal dysraphism has significantly decreased over the last few decades, all over the world; however, the incidence is much higher in developing countries with poor socioeconomic status. The social and economic impact of this disease is not well documented; however, up to 75% of adult survivors may be dependent on parents or other care providers. Aims and Objectives: The aim of this study is to review the demographic profile, clinical pretentions, surgical management and short term outcome of patients presenting with spinal dysraphism Methodology: This is a prospective observational study of cases of spinal dysraphism managed surgically over the period of 2 years from March 2014 to February 2016 in Department of Neurosurgery at Tribhuvan University Teaching Hospital (TUTH), Kathmandu Nepal. Results: Out of total 97 cases, there was male preponderance. In about 40% of population there was no history of proper ANC visit and most of them were from low economic status. Lump on the back was the commonest clinical findings. Lumbar Myelomeningocele was the commonest anatomical location of dysraphism. More than one third of patients needed CSF diversion postoperatively. Conclusion: Myelomeningocele is a common NTDs. Open dysraphism may not always present as a lump. Delay in seeking medical attention may be due to illiteracy. None of the mother had taken folic acid prior to conception.

External Ventricular Drainage (EVD) related infection is one of the most dreaded infections in neurosurgical practice. The primary aim of this study was to assess the incidence of EVD infections in our hospital. In addition, we have made an attempt to evaluate the indication for EVD placement, influence of total drainage time in the risk of catheter infection, the most common bacterial spectra in cerebrospinal fluid (CSF) culture, and their antibiotic sensitivity pattern. This is a retrospective study of all patients who underwent EVD placement over a period of two years. Out of 60 patients who underwent EVD placement, 52 met the inclusion criteria for analysis. The ventricular catheters were in place from 1 to 23 days. Overall shunt infection rate was 36.5%. CSF cell count significantly correlated with the occurrence of a positive CSF culture (unpaired t test, p

Intracranial complications of Chronic Suppurative Otitis Media(CSOM) are common. Brain abscess is the commonest intracranial complication. Traditionally, life threatening brain abscess was managed first and the causative otitis dealt later. However, with the aim of dealing with both at the outset, we have started treating these problems in the same anesthesia setting. Retrospective analysis of the consecutive patients treated simultaneously is presented.

Chłodzenie jest niezbędne dla właściwego funkcjonowania i niezawodności różnorodnych produktów, jak urządzenia elektroniczne, komputery, samochody, systemy laserowe wielkiej mocy, itp. W sytuacji wzrostu obciążenia cieplnego i strumieni ciepła wytwarzanych przez urządzenia przemysłowe, chłodzenie jest jednym z najważniejszych wyzwań występujących w różnych gałęziach przemysłu, transporcie, mikroelektronice, itp. Płynami, które zwykle są używane do odprowadzania ciepła z tych urządzeń są woda, glikol etylenowy i oleje. Nanopłyny, opracowane w ostatnim czasie, wykazują generalnie lepsze charakterystyki przewodnictwa cieplnego niż woda. Przedstawiona praca stanowi podsumowanie badań doświadczalnych nad wymuszonym, konwekcyjnym odprowadzaniem ciepła i charakterystykami przepływu nanopłynu składającego się z wody i cząsteczek Al2O3 (w 1% stężeniu objętościowym) w warunkach laminarnego przepływu współprądowego i przeciwprądowego w płaszczowych i rurowych wymiennikach ciepła. W przedstawionych badaniach użyto cząstek Al2O3 o średnicy ok. 50 nm. Wybrano trzy różne prędkości przepływu masy, opisano wyniki eksperymentów. Wyniki te wskazują, że całkowity współczynnik odprowadzania ciepła i bezwymiarowa liczba Nusselta nanopłynu są, przy tej samej prędkości przepływu masy i temperaturze na wlocie, nieznacznie wyższe, niż dla samego płynu bazowego. Z wyników doświadczalnych wynika, że całkowity współczynnik odprowadzania ciepła wzrasta wraz z prędkością przepływu masy. Pokazano, że gdy wzrasta prędkość przepływu masy, całkowity współczynnik odprowadzania ciepła wraz z bezwymiarową liczbą Nusselta ostatecznie wzrastają, niezależnie od kierunku przepływu. Stwierdzono także, że ze wzrostem prędkości przepływu masy wartość LMTD (średniej logarytmicznej różnicy temperatur) ostatecznie maleje, niezależnie od kierunku przepływu.

Osteoblastoma is a rare and benign osteoid producing primary bone tumor that affects mainly the long bones. It makes 5% of spinal tumors, mostly arising within the posterior elements of the spine within the second and 3rd decades of life. We managed an 18 year old patient with osteoblastoma of C6 vertebra.

A facile, green approach for the synthesis of some new dibenz[1,4]-diazepine-1-one by a three component reaction of Diamine, 1,3 diketone and aromatic aldehyde using oxalic acid as catalyst in water is described. The products are formed in good yields (92–94%). Newly synthesized dibenz [1,4]-diazepine-1-one analogues were evaluated for the anxiolytic activity by the elevated plus maze method. From the activity data it is observed that compounds, 4g, 4h and 4k show promising anxiolytic activity.

Recent evidence suggests that lifestyle factors influence the association between the Melanocortin 4 receptor (MC4R) and Transcription Factor 7-Like 2 (TCF7L2) gene variants and cardio-metabolic traits in several populations; however, the available research is limited among the Asian Indian population. Hence, the present study examined whether the association between the MC4R single nucleotide polymorphism (SNP) (rs17782313) and two SNPs of the TCF7L2 gene (rs12255372 and rs7903146) and cardio-metabolic traits is modified by dietary factors and physical activity. This cross sectional study included a random sample of normal glucose tolerant (NGT) (n = 821) and participants with type 2 diabetes (T2D) (n = 861) recruited from the urban part of the Chennai Urban Rural Epidemiology Study (CURES). A validated food frequency questionnaire (FFQ) was used for dietary assessment and self-reported physical activity measures were collected. The threshold for significance was set at P = 0.00023 based on Bonferroni correction for multiple testing [(0.05/210 (3 SNPs x 14 outcomes x 5 lifestyle factors)]. After Bonferroni correction, there was a significant interaction between the TCF7L2 rs12255372 SNP and fat intake (g/day) (Pinteraction = 0.0001) on high-density lipoprotein cholesterol (HDL-C), where the 'T' allele carriers in the lowest tertile of total fat intake had higher HDL-C (P = 0.008) and those in the highest tertile (P = 0.017) had lower HDL-C compared to the GG homozygotes. In a secondary analysis of SNPs with the subtypes of fat, there was also a significant interaction between the SNP rs12255372 and polyunsaturated fatty acids (PUFA, g/day) (Pinteraction

K Govind Babu,1 Kumar Prabhash,2 Ashok K Vaid,3 Bhawna Sirohi,3 Ravi B Diwakar,4 Raghunadha Rao,5 Madhuchanda Kar,6 Hemant Malhotra,7 Shona Nag,8 Chanchal Goswami,9 Vinod Raina,10 Ravi Mohan111Kidwai Memorial Institute of Oncology, Bangalore, 2Tata Memorial Hospital, Mumbai, 3Artemis Health Institute, Delhi, 4Bangalore Institute of Oncology, Bangalore, 5Nizam Institute of Medical Sciences, Hyderabad, 6B R Singh Hospital, Kolkata, 7Birla Cancer Centre, Jaipur, 8Jehangir Hospital, Pune, 9B P Poddar Hospital and Medical Research Ltd, Kolkata, 10Institute Rotary Cancer Hospital, New Delhi, 11King George Hospital, Visakhapatnam, IndiaBackground: The purpose of this study was to evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in patients with stage IIIB/IV non-small-cell lung cancer.Methods: This multicenter, open-label, Phase II study randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab 200 mg was administered once weekly for 13 weeks during the first two phases with four cycles of chemotherapy and docetaxel 75 mg/m2 and carboplatin (area under the curve 5 mg/mL*min) every 3 weeks for a maximum of four cycles during the concomitant phase. The primary endpoint was objective response rate (sum of complete response and partial response). Secondary endpoints, ie, overall survival and progression-free survival, were estimated using the Kaplan–Meier method. Efficacy was evaluated on the intent-to-treat and efficacy-evaluable sets. Safety was assessed from adverse event and serious adverse event data.Results: The objective response rate was significantly higher in the nimotuzumab group than in the control group in the intent-to-treat population (54% versus 34.5%; P=0.04). A complete response and partial response were achieved in 3.6% and 50% of patients, respectively, in the nimotuzumab group, and in 4% and 30.9% of patients, respectively, in the control group. No significant differences in median progression-free survival and overall survival were observed. Safety profiles were comparable between the two groups.Conclusion: Nimotuzumab plus chemotherapy significantly improved the objective response rate as compared with chemotherapy alone. The combination was safe and well tolerated in patients with stage IIIB/IV non-small-cell lung cancer.Keywords: carboplatin, docetaxel, epidermal growth factor receptor, nimotuzumab, non-small cell lung cancer

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids. Single L-Ala substitutions beyond the Mdm2/(X) binding interfacial residues (i.e., Phe3, Trp7, and Cba10) had minimal effects on target binding, α-helical content, and cellular activity. Similar binding affinities and cellular activities were noted at non-interfacial positions when the template residues were substituted with their d-amino acid counterparts, despite the fact that d-amino acid residues typically ‘break’ right-handed α-helices. d-amino acid substitutions at the interfacial residues Phe3 and Cba10 resulted in the expected decreases in binding affinity and cellular activity. Surprisingly, substitution at the remaining interfacial position with its d-amino acid equivalent (i.e., Trp7 to d-Trp7) was fully tolerated, both in terms of its binding affinity and cellular activity. An X-ray structure of the d-Trp7-modified peptide was determined and revealed that the indole side chain was able to interact optimally with its Mdm2 binding site by a slight global re-orientation of the stapled peptide. To further investigate the comparative effects of d-amino acid substitutions we used linear analogs of ATSP-7041, where we replaced the stapling amino acids by Aib (i.e., R84 to Aib4 and S511 to Aib11) to retain the helix-inducing properties of α-methylation. The resultant analog sequence Ac−Leu−Thr−Phe−Aib−Glu−Tyr−Trp−Gln−Leu−Cba−Aib−Ser−Ala−Ala−NH2 exhibited high-affinity target binding (Mdm2 Kd = 43 nM) and significant α-helicity in circular dichroism studies. Relative to this linear ATSP-7041 analog, several d-amino acid substitutions at Mdm2(X) non-binding residues (e.g., d-Glu5, d-Gln8, and d-Leu9) demonstrated decreased binding and α-helicity. Importantly, circular dichroism (CD) spectroscopy showed that although helicity was indeed disrupted by d-amino acids in linear versions of our template sequence, stapled molecules tolerated these residues well. Further studies on stapled peptides incorporating N-methylated amino acids, l-Pro, or Gly substitutions showed that despite some positional dependence, these helix-breaking residues were also generally tolerated in terms of secondary structure, binding affinity, and cellular activity. Overall, macrocyclization by hydrocarbon stapling appears to overcome the destabilization of α-helicity by helix breaking residues and, in the specific case of d-Trp7-modification, a highly potent ATSP-7041 analog (Mdm2 Kd = 30 nM; cellular EC50 = 600 nM) was identified. Our findings provide incentive for future studies to expand the chemical diversity of macrocyclic α-helical peptides (e.g., d-amino acid modifications) to explore their biophysical properties and cellular permeability. Indeed, using the library of 50 peptides generated in this study, a good correlation between cellular permeability and lipophilicity was observed.

Context: Work-related musculoskeletal disorders (WRMSD) had been previously reported to have a high prevalence among dentists in different parts of the world. Aims: The study aimed to assess the prevalence of self-reported WRMSD among dental professionals in India. Material and Methods: A cross-sectional survey of 646 dentists (response rate of 82.97%) was done using self-administered questionnaire which consisted of 27 items based on Nordic questionnaire for screening WRMSDs. Additional items of the questionnaire were added after preliminary content validation from six experienced dentists. Participant socio-demographic characteristics, work-related physical load characteristics, musculoskeletal symptom characteristics were evaluated. Statistical analysis used: All data were analyzed descriptively using percentiles and association between work-related physical load and WRMSD prevalence was done using Chi-square test. Results: All 536 dentists had at least one work-related musculoskeletal symptom in the previous year with an overall period prevalence rate of 100%. The type of symptoms present were pain (99.06%), stiffness (3.35%), fatigue (8.39%), discomfort (12.87%), clicks/sounds (4.1%), and other neurogenic (20.14%). The regions of symptoms were neck (75.74%), wrist/hand (73.13%), lower back (72.01%), shoulder (69.4%), hip (29.85%), upper back (18.65%), ankle (12.31%), and elbow (7.46%). Number of regions affected were two (82.83%), three (51.86%), four, or more (15.11%). Recurrent symptoms were present in 76.11%. Strong association was noted between sustained work postures and symptom regions for pain in WRMSD. Conclusion: The study found an overall one-year period prevalence rate of 100% for WRMSDs among Indian dentists. Measures for improving education and ergonomic evaluations are indicated on a large scale to prevent decline in work performance and incidence of WRMSDs among Indian dentists.

Background and Aim: Anaesthesia for cleft surgery in children is associated with a variety of airway related problems. This study aims to review the frequency of associated anomalies and other conditions as well as perioperative respiratory complications during the cleft lip/palate repair surgeries. Methods: An audit of 1000 cleft surgeries in children enrolled under "Smile Train" is presented. Following informed consent, general anaesthesia was induced with endotracheal (ET) intubation using halothane in O 2 and/or intravenous thiopentone 5 mg/kg or propofol 1.5 mg/kg, suxamethonium 1.5 mg/kg or rocuronium 0.8 mg/kg and maintained with halothane/isoflurane 0.4-1% in 50% N 2 O in O 2 with rocuronium. The observational data regarding the occurrence of perioperative complications in 1000 cleft surgeries are mentioned as mean (standard deviation), number and percentage as appropriate. ′Two sample t-test between percentage′ is applied for significance. Results: The frequency of isolated cleft lip was 263 (36.4%), cleft palate 183 (25.3%) and combined defect 277 (38.3%) of the operated cases. Other congenital anomalies were present in 21 (2.8%) of the children. The intraoperative airway complications occurred in 13 (2.4%) of cleft lip and 40 (8.7%) of cleft palate repairs (P < 0.05). Post-operative respiratory complications were observed in 9 (1.7%) and 34 (7.4%) patients of cleft lip and palate repairs respectively (P < 0.05). Mortality occurred post-operatively in 2 (0.2%) of cleft repairs (n = 1000). Conclusion: Cleft deformities in children when associated with other congenital anomalies or respiratory problems pre-dispose them to difficult airway and pulmonary complications. Frequency of perioperative respiratory complications were significantly higher with cleft palate repair than with cleft lip repair. Anaesthetic expertise, optimum monitoring facility and specialised post-operative care is necessary to decrease the morbidity.