Therapeutic detoxification of quercetin for aflatoxin B1-related toxicity: Roles of oxidative stress, inflammation, and metabolic enzymes.

Aflatoxins (AFTs), a type of mycotoxin mainly produced by Aspergillus parasiticus and Aspergillus flavus, could be detected in food, feed, Chinese herbal medicine, grain crops and poses a great threat to public health security. Among them, aflatoxin B1 (AFB1) is the most toxic one. Exposure to AFB1 poses various health risks to both humans and animals, including the development of chronic inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, and cancer. The molecular mechanisms underlying these risks are intricate and dependent on specific contexts. This review primarily focuses on summarizing the protective effects of quercetin, a natural phenolic compound, in mitigating the toxic effects induced by AFB1 in both in vitro experiments and animal models. Additionally, the review explores the molecular mechanisms that underlie these protective effects. Quercetin has been demonstrated to not only have the direct inhibitory action on the production of AFTs from Aspergillus, both also possess potent ameliorative effects against AFB1-induced cytotoxicity, hepatotoxicity, and neurotoxicity. These effects are attributed to the inhibition of oxidative stress, mitochondrial dysfunction, mitochondrial apoptotic pathway, and inflammatory response. It could also directly target several metabolic enzymes (i.e., CYP3As and GSTA1) to reduce the production of toxic metabolites of AFB1 within cells, then reduce AFB1-induced cytotoxicity. In conclusion, this review highlights quercetin is a promising detoxification agent for AFB1. By advancing our understanding of the protective mechanisms offered by quercetin, we aim to contribute to the development of effective detoxification agents against AFB1, ultimately promoting better health outcomes.

Synthesizing pectin-crosslinked gum ghatti hydrogel for efficient adsorptive removal of malachite green.

Pectin-crosslinked gum ghatti hydrogel (PGH) has been synthesized utilizing pectin and gum ghatti through an uncomplicated and inexpensive copolymerization method. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM-elemental mapping), Brunauer-Emmett-Teller (BET), and X-ray photoelectron spectroscopy (XPS) characterization techniques have been employed to determine various structural, chemical and compositional characteristics of fabricated PGH. Three different weight ratios (1:1, 2:1, or 1:2 for pectin and gum ghatti, respectively) were employed to synthesize three distinct types of PGH. Swelling studies has been done to determine the best ratios for PGH fabrication. PGH has been assessed as an adsorbent for the removal of malachite green dye from aqueous solutions. The effects of PGH dosage (100-400 mg/L), dye concentration (10-160 mg/L), pH (2-9 pH), adsorption time (0-480 min), and temperature (25-55 °C) has been examined through batch solutions. According to Langmuir isotherm analysis, the maximum adsorption capacity is 658.1 mg/g. By using pseudo-second-order kinetics and the Freundlich adsorption isotherm, the adsorption process could be well explained. After five consecutive cycles, PGH had an adsorption percentage of 86.917 % for the malachite green dye. It is safe for the environment and may be used to remove malachite green (MG) dye from aqueous solutions.

Accessory Tibionavicular Muscle: An Unusual Cause of Medial Ankle Pain.

Accessory or anomalous muscles around the ankle are not uncommon and are usually asymptomatic. They are traditionally encountered during imaging undertaken for evaluation of ankle pain. We reported the first case of a new accessory muscle in the anteromedial part of the ankle with associated partial thickness tear in an 18-year-old football player presenting as symptomatic pathology. In this article, we described the role of cross-sectional imaging in its diagnosis including successful management of the condition with ultrasound-guided platelet-rich plasma therapy and review-associated literature.

The known, unknown, and the intriguing about members of a critically endangered traditional medicinal plant genus Aconitum.

Humanity will always be indebted to plants. In the ongoing scientific era, the 'Herbal Revolution' has helped discover several valuable medicinal plants and associated novel secondary metabolites from the diverse unexplored ecosystems, treating several diseases via phytotherapy. The Aconitum genus comprises several economically-important poisonous mountainous medicinal plant species whose unique biodiversity is on the verge of extinction due to illegal human intervention triggered habitat loss, over-harvesting, and unrestricted trading. Owing to its vast diversity of diterpene alkaloids, most species are extensively used to treat several ailments in rural parts of the world. Irrespective of this, many unexplored and intriguing prospects exist to understand and utilize this critical plant for human benefit. This systematic review tries to fill this gap by compiling information from the sporadically available literature known for ~300 Aconitum spp. regarding its nomenclature and classification, endangerment, plant morphology, ploidy, secondary metabolites, drug pharmacokinetics, conservation, and omics-based computational studies. We also depicted the disparity in the studied model organisms for this diverse genus. The absence of genomic/metagenomic data is becoming a limiting factor in understanding its plant physiology, metabolic pathways, and plant-microbes interactions, and therefore must be promoted. Additionally, government support and public participation are crucial in establishing conservation protocols to save this plant from endangerment.

Transcriptome Analysis of Podoscypha petalodes Strain GGF6 Reveals the Diversity of Proteins Involved in Lignocellulose Degradation and Ligninolytic Function.

The present study reports transcriptomic profiling of a Basidiomycota fungus, Podoscypha petalodes strain GGF6 belonging to the family Podoscyphaceae, isolated from the North-Western Himalayan ranges in Himachal Pradesh, India. Podoscypha petalodes strain GGF6 possesses significant biotechnological potential as it has been reported for endocellulase, laccase, and other lignocellulolytic enzymes under submerged fermentation conditions. The present study attempts to enhance our knowledge of its lignocellulolytic potential as no previous omics-based analysis is available for this white-rot fungus. The transcriptomic analysis of P. petalodes GGF6 reveals the presence of 280 CAZy proteins. Furthermore, bioprospecting transcriptome signatures in the fungi revealed a diverse array of proteins associated with cellulose, hemicellulose, pectin, and lignin degradation. Interestingly, two copper-dependent lytic polysaccharide monooxygenases (AA14) and one pyrroloquinolinequinone-dependent oxidoreductase (AA12) were also identified, which are known to help in the lignocellulosic plant biomass degradation. Overall, this transcriptome profiling-based study provides deeper molecular-level insights into this Basidiomycota fungi, P. petalodes, for its potential application in diverse biotechnological applications, not only in the biofuel industry but also in the environmental biodegradation of recalcitrant molecules. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01037-6.

The Origin and Clinical Relevance of Yoga Nidra.

Yoga nidra, also known as 'yogic sleep', is a simplified form of an ancient tantric relaxation technique. The most general description of the practice is that it combines guided mental imagery with a specific yoga posture called Shavasana (or "corpse pose"). The goal of yoga nidra is to promote a profound state of relaxation, which differs from sleep inasmuch as there is still an awareness of one's surroundings. While several components of the practice have been known since ancient times, it was not until the 1960s that an updated and systematized system of practice was introduced to the public through the writings of Swami Satyananda Saraswati. Unlike other schools of yoga, which emphasize concentration or contemplation, yoga nidra's goal is complete relaxation. As such, its advocates claim that it is suitable for all individuals, from beginners to advanced practitioners of yoga. The calm inner stillness induced by yoga nidra is claimed by practitioners to be an effective stress management tool as well as a means for attaining greater receptivity to personal resolutions. These resolutions can range from the goal of achieving self-transformation, enhancing creativity, or improving one's learning ability. Additionally, yoga nidra is claimed to promote beneficial changes in physiological and mental health. The following narrative review summarizes the basic steps used to achieve the final state of yoga nidra relaxation as well as some recent experimental findings regarding its physiological and psychological effects. Standard research databases were searched for relevant articles. Clinical studies have shown that yoga nidra meditation is associated with positive physiological changes, including improvements in several hematological variables, red blood cell counts, blood glucose levels, and hormonal status. Two neuroimaging studies have shown that yoga nidra produces changes in endogenous dopamine release and cerebral blood flow, a further confirmation that its effects on the CNS are objectively measurable. The practice has also been shown to reduce psychometrically measured indices of mild depression and anxiety, although these benefits were not shown in an experimental study to extend to severe depression or severe anxiety.

Hypoalbuminemia and not undernutrition predicts high-dose methotrexate-induced nephrotoxicity in children with acute lymphoblastic leukemia in resource-constrained centers.

BACKGROUND: The standard practice to mitigate high-dose methotrexate (HD-MTX)-induced nephrotoxicity (HMN) in acute lymphoblastic leukemia (ALL) is to monitor levels until serum MTX falls below a predefined threshold. It is not feasible in most resource-constrained centers. Literature on the various factors affecting HMN in these centers is limited, retrospective, and heterogeneous. Though hypoalbuminemia has been postulated as a risk factor for HMN, the relationship of undernutrition with HMN has not been studied. PROCEDURE: This prospective observational study consecutively enrolled children < 12 years old with ALL receiving HD-MTX. Children with preexisting renal disease and exposed to nephrotoxic drugs two weeks preceding HD-MTX infusion were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. Solitary MTX levels at 36 hours (MTX36) were outsourced, and 6-8 doses of leucovorin were given six-hourly. Hydration was continued till last dose of leucovorin. Various factors affecting HMN (rise in creatinine to 1.5 times baseline) were recorded: age, sex, type of ALL, risk group of ALL, first dose of MTX, dose of MTX, undernourishment, serum protein, and albumin along with C-reactive protein and MTX36 levels. RESULTS: Forty-four children who received 150 HD-MTX cycles were analyzed. HMN was seen in 14% of cycles. On univariate analysis, undernourishment, MTX36 levels, hypoproteinemia, and hypoalbuminemia were significantly associated with HMN. On multivariate analysis, hypoalbuminemia and MTX36 levels significantly predicted the development of HMN with odds ratios of 4.71 and 1.45. CONCLUSION: Hypoalbuminemia and solitary serum MTX levels predict HMN in centers where serial MTX level monitoring is not feasible.

Nitrogen Fixation Influenced by Phosphorus and Nitrogen Availability in the Benthic Bloom-forming Cyanobacterium Hydrocoleum sp. Identified in a Temperate Marine Lagoon.

The nitrogen-fixing, non-heterocystous cyanobacterium Hydrocoleum sp. (Oscillatoriales) is a common epiphytic and benthic bloom-former in tropical and subtropical shallow water systems but shares high phylogenetic similarity with the planktonic, globally important diazotroph Trichodesmium. Multiphasic observations in this study resulted in unexpected identification of Hydrocoleum sp. in mass accumulations in a coastal lagoon in the Western temperate North Atlantic Ocean. Hydrocoleum physiology was examined in situ through measurements of N2 and CO2 fixation rates and expression of genes involved with N2 fixation, CO2 fixation, and phosphorus (P) stress. Bulk N2 fixation rates and Hydrocoleum nifH expression peaked at night and were strongly suppressed by dissolved inorganic nitrogen (DIN). The expression of high affinity phosphate transporter (pstS) and alkaline phosphatase (phoA) genes of Hydrocoleum was elevated during the night and negatively responded to phosphate amendments, as evidence that these mechanisms contribute to P acquisition during diazotrophic growth of Hydrocoleum in situ. This discovery at the edge of the previously known Hydrocoleum habitat range in the warming oceans raises intriguing questions about diazotrophic cyanobacterial adaptations and transitions on the benthic-pelagic continuum.

Remediation of Cd and Cu contaminated water and soil using novel nanomaterials derived from sugar beet processing- and clay brick factory-solid wastes.

Producing nanomaterials from hazardous wastes for water and soil treatment is of great concern. Here, we produced and fully characterized two novel nanomaterials from sugar beet processing (SBR)- and brick factory-residuals (BFR) and assed their ability for Cd and Cu sorption in water and reducing metal availability in a contaminated soil. The SBR removed up to 99% of Cu and 91% of Cd in water, and exhibited a significantly faster and higher sorption capacity (qmax (g kg-1) = 1111.1 for Cu and 33.3 for Cd) than BFR (qmax (g kg-1) = 33.3 for Cu and 10.0 for Cd), even at acidic pH. Soil metal availability was significantly reduced by SBR (up to 57% for Cu and 86% for Cd) and BFR (up to 36% for Cu and 68% for Cd) compared to the unamended soil. The higher removal efficacy of SBR over BFR could be attributed to its higher alkalinity (pH = 12.5), carbonate content (82%), and specific surface area, as well as the activity of hydroxyl -OH and Si-O groups. The nano-scale SBR and BFR, the former particularly, are novel, of low cost, and environmental friendly amendments that can be used for the remediation of metal-contaminated water and soil.

Role of Phytomolecules in the Treatment of Obesity: Targets, Mechanisms and Limitations.

Obesity has become a worldwide health problem. It triggers additional co-morbidities like cardiovascular diseases, cancer, depression, sleep disorders, gastrointestinal problems and many more. Excess accumulation of fat in obesity could be caused by many factors like sedentary lifestyle, consumption of high-fat diet, genetic predisposition, etc. Imbalanced energy metabolism i.e., greater energy consumption than utilisation, invariably underlies obesity. Considering the high prevalence and continuous, uncontrolled increase of this major public health issue, there is an urgent need to find appropriate therapeutic agents with minimal or no side effects. The high prevalence of obesity in recent years has led to a surge in the number of drugs available in the market that claim to control obesity. Although there is a long list of medicines and management strategies that are available, selecting the right therapeutic intervention and feasible management of obesity is a challenge. Several phytochemicals like hydroxycitric acid, flavonoids, tannins, anthocyanins, phytohaemagglutinin, thymoquinone and epigallocatechin gallate have been shown to possess promising anti-obesity properties. However, studies providing information on how various phytochemicals exert their anti-obesity effects are inadequate. This calls for more experimentation in this less explored area of research. Additionally, the complication of obesity arises when it is a result of multiple factors and associated with a number of co-morbidities. In order to handle such complexities, combinatorial therapeutic interventions become effective. In this review, we have described the medicinal chemistry of different highly effective phytochemicals which can be used in the effective treatment and management of obesity.

In-situ crosslinked hydrogel based on amidated pectin/oxidized chitosan as potential wound dressing for skin repairing.

Hydrogel can provide a favorable moisture environment for skin wound healing. In this study, a novel in-situ crosslinked injectable hydrogel was prepared using the water-soluble amidated pectin (AP) and oxidized chitosan (OC) through Schiff-base reaction without any chemical crosslinker. The influence of AP content on the properties of the hydrogel was systemically investigated. It showed that gelation time, pore structure, swelling capability and degradability of the hydrogel can be tuned by varying the content of amine and aldehyde groups from AP and OC. All the porous hydrogels with various AP contents (65%, 70%, and 80%) presented desirable gelation time, swelling property, high hemocompatibility and biocompatibility. Particularly, AP-OC-65 hydrogel presented superior swelling capability and better hemo- and bio-compatibility, owing to more residual amine sites in the hydrogel. Therefore, the injectable AP-OC-65 hydrogel has a greater potential for application to wound dressing or skin substitute.

A Comprehensive Toxicological Assessment of Fulvic Acid.

Fulvic acid (FA), a humic substance, has several nutraceutical properties, including anti-inflammation, antimicrobial, and immune regulation abilities. However, systematic safety assessment remains insufficient. In the present study, a battery of toxicological studies was conducted per internationally accepted standards to investigate the genotoxicity and repeated-dose oral toxicity of FA. Sprague-Dawley (SD) rats or ICR mice were used. Compared to the control group, there were no significant changes (all p > 0.05) in all FA treatment groups in the bacterial reverse mutation test, in vitro mammalian chromosome aberration test, in vivo sperm shape abnormality assay, and in vivo mouse micronucleus assay. The acute toxicity test showed that no mortality or toxic effect was observed following oral administration of the maximum dose of 5,000 mg/kg BW/day to mice or rats. A 60-day subchronic study was conducted at 0 (control), 200, 1,000, and 5,000 mg/kg/day. Compared to the control group, there were no significant changes (all p > 0.05) in the body weights, feed consumption, clinical signs, hematology, clinical chemistry, organ weights, or histopathology examinations. In conclusion, the no-observed-adverse-effect-level (NOAEL) of FA supplementation from the 60-day study was determined to be 5,000 mg/kg body weight/day, the highest dose tested. Our findings suggest that the oral administration of FA may have higher safety.

Polymyxins-Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment.

The emergence of antimicrobial resistance in Gram-negative bacteria poses a huge health challenge. The therapeutic use of polymyxins (i.e., colistin and polymyxin B) is commonplace due to high efficacy and limiting treatment options for multidrug-resistant Gram-negative bacterial infections. Nephrotoxicity and neurotoxicity are the major dose-limiting factors that limit the therapeutic window of polymyxins; nephrotoxicity is a complication in up to ~60% of patients. The emergence of polymyxin-resistant strains or polymyxin heteroresistance is also a limiting factor. These caveats have catalyzed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and resistant organisms and/or minimize the unwanted side effects. Curcumin-an FDA-approved natural product-exerts many pharmacological activities. Recent studies showed that polymyxins-curcumin combinations showed a synergistically inhibitory effect on the growth of bacteria (e.g., Gram-positive and Gram-negative bacteria) in vitro. Moreover, curcumin co-administration ameliorated colistin-induced nephrotoxicity and neurotoxicity by inhibiting oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. In this review, we summarize the current knowledge-base of polymyxins-curcumin combination therapy and discuss the underlying mechanisms. For the clinical translation of this combination to become a reality, further research is required to develop novel polymyxins-curcumin formulations with optimized pharmacokinetics and dosage regimens.

Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX).

A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein, we describe an analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold increase in affinity and detailed structural information for the resulting complex, providing an efficient and broadly applicable approach to early fragment development.

Clinically Significant Gains in Skillful Grasp Coordination by an Individual With Tetraplegia Using an Implanted Brain-Computer Interface With Forearm Transcutaneous Muscle Stimulation.

OBJECTIVE: To demonstrate naturalistic motor control speed, coordinated grasp, and carryover from trained to novel objects by an individual with tetraplegia using a brain-computer interface (BCI)-controlled neuroprosthetic. DESIGN: Phase I trial for an intracortical BCI integrated with forearm functional electrical stimulation (FES). Data reported span postimplant days 137 to 1478. SETTING: Tertiary care outpatient rehabilitation center. PARTICIPANT: A 27-year-old man with C5 class A (on the American Spinal Injury Association Impairment Scale) traumatic spinal cord injury INTERVENTIONS: After array implantation in his left (dominant) motor cortex, the participant trained with BCI-FES to control dynamic, coordinated forearm, wrist, and hand movements. MAIN OUTCOME MEASURES: Performance on standardized tests of arm motor ability (Graded Redefined Assessment of Strength, Sensibility, and Prehension [GRASSP], Action Research Arm Test [ARAT], Grasp and Release Test [GRT], Box and Block Test), grip myometry, and functional activity measures (Capabilities of Upper Extremity Test [CUE-T], Quadriplegia Index of Function-Short Form [QIF-SF], Spinal Cord Independence Measure-Self-Report [SCIM-SR]) with and without the BCI-FES. RESULTS: With BCI-FES, scores improved from baseline on the following: Grip force (2.9 kg); ARAT cup, cylinders, ball, bar, and blocks; GRT can, fork, peg, weight, and tape; GRASSP strength and prehension (unscrewing lids, pouring from a bottle, transferring pegs); and CUE-T wrist and hand skills. QIF-SF and SCIM-SR eating, grooming, and toileting activities were expected to improve with home use of BCI-FES. Pincer grips and mobility were unaffected. BCI-FES grip skills enabled the participant to play an adapted "Battleship" game and manipulate household objects. CONCLUSIONS: Using BCI-FES, the participant performed skillful and coordinated grasps and made clinically significant gains in tests of upper limb function. Practice generalized from training objects to household items and leisure activities. Motor ability improved for palmar, lateral, and tip-to-tip grips. The expects eventual home use to confer greater independence for activities of daily living, consistent with observed neurologic level gains from C5-6 to C7-T1. This marks a critical translational step toward clinical viability for BCI neuroprosthetics.

A High Definition Noninvasive Neuromuscular Electrical Stimulation System for Cortical Control of Combinatorial Rotary Hand Movements in a Human With Tetraplegia.

OBJECTIVE: Paralysis resulting from spinal cord injury (SCI) can have a devastating effect on multiple arm and hand motor functions. Rotary hand movements, such as supination and pronation, are commonly impaired by upper extremity paralysis, and are essential for many activities of daily living. In this proof-of-concept study, we utilize a neural bypass system (NBS) to decode motor intention from motor cortex to control combinatorial rotary hand movements elicited through stimulation of the arm muscles, effectively bypassing the SCI of the study participant. We describe the NBS system architecture and design that enabled this functionality. METHODS: The NBS consists of three main functional components: 1) implanted intracortical microelectrode array, 2) neural data processing using a computer, and, 3) a noninvasive neuromuscular electrical stimulation (NMES) system. RESULTS: We address previous limitations of the NBS, and confirm the enhanced capability of the NBS to enable, in real-time, combinatorial hand rotary motor functions during a functionally relevant object manipulation task. CONCLUSION: This enhanced capability was enabled by accurate decoding of multiple movement intentions from the participant's motor cortex, interleaving NMES patterns to combine hand movements, and dynamically switching between NMES patterns to adjust for hand position changes during movement. SIGNIFICANCE: These results have implications for enabling complex rotary hand functions in sequence with other functionally relevant movements for patients suffering from SCI, stroke, and other sensorimotor dysfunctions.

Vehicle Tracking in Wide Area Motion Imagery via Stochastic Progressive Association Across Multiple Frames (SPAAM).

Vehicle tracking in Wide Area Motion Imagery (WAMI) relies on associating vehicle detections across multiple WAMI frames to form tracks corresponding to individual vehicles. The temporal window length, i.e., the number M of sequential frames, over which associations are collectively estimated poses a trade-off between accuracy and computational complexity. A larger M improves performance because the increased temporal context enables the use of motion models and allows occlusions and spurious detections to be handled better. The number of total hypotheses tracks, on the other hand, grows exponentially with increasing M, making larger values of M computationally challenging to tackle. In this paper, we introduce SPAAM an iterative approach that progressively grows M with each iteration to improve estimated tracks by exploiting the enlarged temporal context while keeping computation manageable through two novel approaches for pruning association hypotheses. First, guided by a road network, accurately co-registered to the WAMI frames, we disregard unlikely associations that do not agree with the road network. Second, as M is progressively enlarged at each iteration, the related increase in association hypotheses is limited by revisiting only the subset of association possibilities rendered open by stochastically determined dis-associations for the previous iteration. The stochastic disassociation at each iteration maintains each estimated association according to an estimated probability for confidence, obtained via a probabilistic model. Associations at each iteration are then estimated globally over the M frames by (approximately) solving a binary integer programming problem for selecting a set of compatible tracks. Vehicle tracking results obtained over test WAMI datasets indicate that our proposed approach provides significant performance improvements over state of the art alternatives.

Guar gum-crosslinked-Soya lecithin nanohydrogel sheets as effective adsorbent for the removal of thiophanate methyl fungicide.

Rapid increase in use of fungicides for the agricultural and industrial purposes has marked the deterioration of water resources which ultimately affects the human life. Accordingly, various attempts have been made in the removal of these noxious compounds. In the same context, we are presenting biopolymers based nanohydrogel sheets; guar gum-crosslinked-Soya lecithin nanohydrogel sheets (GG-crosslinked-SY NHS) used for the effective removal of a fungicide; thiophanate methyl from aqueous solution. Guar gum and soya lecithin were employed as the biopolymers in the fabrication of nanohydrogel sheets due to their non- toxic nature, easy availability, cheapness and significant properties. Due to the presence of highly reactive functional groups onto the surface of GG-crosslinked-SY NHS, good adsorption results have been obtained. Maximum adsorption capacity of 59.205mg/g was observed with 20mg GG-crosslinked-SY NHS and 25ppm thiophanate methyl solution concentration as calculated from the Langmuir isotherm. Results showed that neutral pH favoured the adsorption process. Kinetics results were indicative of the physical interactions between the thiophanate methyl and GG-crosslinked-SY NHS surface. Thermodynamic results have shown the spontaneous and endothermic adsorption process.

Sorafenib inhibits proliferation and invasion in desmoid-derived cells by targeting Ras/MEK/ERK and PI3K/Akt/mTOR pathways.

Desmoid tumors (DTs) are unusual neoplasms of mesenchymal origin that exhibit locally invasive behavior. Surgical resection is the initial treatment of choice for DTs. For patients with recurrent or unresectable disease, however, medical options are limited. Sorafenib is a multikinase inhibitor with known antitumor activity in various cancers via suppression of the PI3K/Akt/mTOR pathway. Here, we examined the effects of sorafenib on patient-derived DT cell lines, with the aim of characterizing the efficacy and molecular mechanism of action. Early passage DT-derived cells were treated with increasing doses of sorafenib (0-10 µM) and demonstrated up to 90% decrease in proliferation and invasion relative to controls. Signaling arrays identified multiple potential targets of sorafenib in the Ras/MEK/ERK and PI3K/Akt/mTOR signaling cascades. Immunoblot analysis revealed that sorafenib inhibited Akt, MEK and ERK phosphorylation, and this effect correlated with inhibition of total Akt and total MEK, while total ERK levels remained unchanged. Sorafenib also inhibited 4E-BP1 phosphorylation, and this effect correlated with decrease of p-eIF4E and total eIF4E. Finally, in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus, sorafenib decreased phosphorylation of the ribosomal protein and mTOR effector S6K in an additive manner. Taken together, our results suggest that sorafenib suppresses DT proliferation and invasion via inhibition of Ras/MEK/ERK and PI3K/Akt/mTOR signaling pathways with additional effects on translation. Sorafenib may be a promising therapeutic option in the treatment of DTs. Additional studies in DT patients are warranted to examine the efficacy of combination therapy using sorafenib.

Exploring determinants of care-seeking behaviour of oral cancer patients in India: A qualitative content analysis.

BACKGROUND: A major public health concern in India is the high morbidity and mortality rates of oral cancer because of late diagnosis. Among the several determinants of this late diagnosis, the most important is the healthcare-seeking behaviour of the oral cancer patients. The aim of this study was to explore the care-seeking behaviour and its determinants among oral cancer patients. METHODS: A face-to-face in-depth interview was conducted among 70 oral cancer patients using a semi-structured questionnaire, and qualitative content analysis of the results was performed. RESULTS: All the patients had squamous-cell carcinoma and none had attended any screening programme. The most common site affected was the buccal mucosa with a non-healing wound. Most of the patients contacted a doctor available nearby; only 7% of patients consulted a dentist. Only one patient approached a traditional healer. The median patient delay was 30 (4-365) days and the professional delay was 40 (4-650) days. Enablers included determinants such as increasing symptoms (80%), influence of the society (74%), fear (10%), and social media (3%). The main barriers were lack of awareness (97%), hope that the lesion will heal spontaneously (90%), lack of perception of seriousness (64%), financial constraints (55%), provider switching (47%), and missed diagnosis (44%). CONCLUSION: The care-seeking path among oral cancer patients is complex, customised, and influenced by multiple patient-related and system-related factors.