HYENA detects oncogenes activated by distal enhancers in cancer.

Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm "HYENA" to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.

Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.

Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3-Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB-510 showed an average diameter of 96 ± 3 nm, a zeta potential of -17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA-MB-468, SUM-149, MCF-7, and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK, and c-Myc levels. Importantly, bi-weekly treatment of Balb/c wild-type mice harboring EAC cells with HSB-510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for the successful targeting of breast cancer and potentially other cancer types.

Effect of Metal-Cored Filler Wire on Surface Morphology and Micro-Hardness of Regulated Metal Deposition Welded ASTM A387-Gr.11-Cl.2 Steel Plates.

Environmental and human-friendly welding is the need of the hour. In this context, this study explores the application of the regulated metal deposition (RMD) technique for ASTM A387-Gr.11-Cl.2 steel plates. To examine the effect of metal-cored filler wire (MCFW), MEGAFIL 237 M was employed during regulated metal deposition (RMD) welding of 6 mm thick ASTM A387-Gr.11-Cl.2 steel plates. The welding was carried out at an optimized current (A) of 100 A, voltage (V) of 13 V, and gas flow rate (GFR) of 21 L/min. Thereafter, the as-welded plates were examined for morphological changes using optical microscopy. Additionally, the micro-hardness of the as-welded plates was measured to make corroboration with the obtained surface morphologies. In addition to this, the as-welded plates were subjected to heat treatment followed by surface morphology and micro-hardness examination. A comparison was made between the as-welded and heat-treated plates for their obtained surface morphologies and microhardness values. During this, it was observed that the weld zone of as-welded plates has a dendritic surface morphology which is very common in fusion-based welding. Similarly, the weld zone of heat-treated plates has a finer and erratic arrangement of martensite. Moreover, the obtained surface morphologies in the weld zone of as-welded and heat-treated plates have been justified by their respective hardness values of 1588.6 HV and 227.3 HV.

Reconstruction of cranial defect with patient-specific implants: Four different cost-effective techniques.

Cranial defects secondary to trauma, surgery or pathological causes, result in large cranial imperfection, which affects the appearance of the patient as well as results in sinking flap syndrome. Rehabilitation of such a defect can be done using prosthetic options like custom-made polymethyl methacrylate (PMMA) cranial prosthesis or surgical options like outer table calvarial graft segments. It is usually observed that the conventional moulage impression of the defective site is the most difficult task. The accuracy of the prosthesis is affected by conventional moulage impression, a moulage cast of the defect and techniques of fabricating wax pattern. Orthodox method is to mark the tentative outline of the defect and make a conventional moulage impression of the site. However, this is an arbitrary method which offers challenges to accurate replication of the borders of the defect. Recently, medical imaging and digital modeling in dentistry have paved the way for digital dental practice and additive manufacturing replacing most manual or subtractive procedures. The use of computerized tomography scan to obtain a 3 D digital image of cranial defect for fabricating a replica with rapid prototyping has markedly improved the accuracy at the margin of the defect/prosthesis interface, resulting in a better fit and optimal contour lending itself to the improved esthetic outcome. It is a more reliable method of fabricating a cranial implant prosthesis, which requires minimum adjustment when the patient is on the OT table. These case reports compare rehabilitation of cranial defect with custom-made PMMA cranial prosthesis using the conventional methods as well as rapid prototyping technique. It is seen that the rapid prototyping method is expensive but accurate and gives a better esthetic outcome.

Foam-Based Drug Delivery: A Newer Approach for Pharmaceutical Dosage Form.

Foam is a dispersal of gas in solid foam or liquid foam. Solid foams are generally formed through quick curing of liquid foams. Because of their positive characteristics, simplicity of application, and improved patient acceptability/compliance, foams are an appealing and promising delivery strategy for medical, cosmetic, and pharmaceutical, applications. Recent breakthroughs in topical foams for cosmetic and dermal applications are described here, as well as categorization based on foam formulation and recent assessment techniques of critical physical properties of the topical foam. Despite the expanding amount of knowledge on topical foams for cutaneous applications, the majority of research has focused on the stability and structure of foam in contact with solid nonporous surfaces. It is still difficult to figure out how such foams destabilize when they come into touch with porous surfaces like skin or skin-like membranes. The foam-covered wide surface area and easily applied to the affected area. This type of delivery system also eliminates the chance of secondary infection that is associated with ointment and creams, which need to be applied to the affected area with help of fingers or an applicator.

Rehabilitation of Auricular Defect with Implant-Retained Auricular Prosthesis - A Case Report.

RATIONALE: Maxillofacial defect is of great concern physically, emotionally, and psychologically for a patient. However, it is an even bigger challenge for a team attempting rehabilitation, as a crucial decision has to be made between surgical approach and/or prosthetic rehabilitation. However, if both are combined, it will result in best of esthetics and function with ease of maintainance, resulting in a sucessful rehabilitation. This case report represents a case of auricular defect rehabilitated with a combination of implants and bar-retained silicone prosthesis. PATIENT CONCERN: A 38-year-old male patient with right auricular defect reported with the main concern of esthetic rehabilitation of a lost part of the external ear. DIAGNOSIS: With through evaluation and examination, a diagnosis of acquired partial auricular defect of the right side secondary to trauma was established. TREATMENT: An implant-retained auricular prosthesis was planned for this case. Surgically, three intraoral implants were placed in the mastoid bone, and after healing, bar framework was fabricated and attached. Finally, silicone prosthesis was fabricated and delivered to the patient. OUTCOME: A successful rehabilitation was carried out in this case using implants and bar attachment for retention of the silicone prosthesis. This prosthesis provided excellent retention and restored the appearance and confidence of the patient. TAKE-AWAY LESSONS: Rehabilitation of the auricular defect can be carried out with surgical approach, which involves multiple surgeries, and still, the results may not be esthetically favorable. Prosthetic rehabilitation is an option, but retention is generally a hindrance. However, implant-retained prosthesis has really paved a way for rehabilitation of the maxillofacial defect esthetically and more reliably. Cone-beam computerized tomography (CT) can be used for planning and evaluation instead of CT, which will save the patient from a lot of radiation exposure. Hence, in the maxillofacial defect, attempts should be made to explore the option of implant-retained prosthesis.

Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19869-5.

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

Parvalbumin-positive (PV+ ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV+ interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV+ interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV+ interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV+ interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.

Prosthetic Management of Microstomia with Customized Dynamic Splint.

Microstomia is a clinical condition of reduced mouth opening that can be acquired or congenital in origin. Problems associated with microstomia can be related to function, esthetics, or both. Management of microstomia due to facial burns is complex due to the presence of hypertrophic and contracture scars. Available treatment options can be broadly classified as surgical, nonsurgical, or both. Splints can be used to prevent the contraction of perioral musculature or to recuperate lost mouth opening. Various intraoral or extraoral, tooth-borne or tissue-borne, and static or dynamic appliances are in clinical use, but their designs are case specific. This case report explains the management of microstomia secondary to facial burns by using a dynamic splint in combination with intralesional injections of triamcinolone acetonide and hyaluronidase.

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.

Total Synthesis of Indolizidine Alkaloids via Nickel-Catalyzed (4 + 2) Cyclization.

A Ni-catalyzed (4 + 2) cycloaddition of alkynes and azetidinones toward piperidinones was used as key reaction in the enantioselective synthesis of naturally occurring indolizidine alkaloids. The reaction benefits from the use of an easily accessible azetidinone as an advanced and divergent intermediate to build the indolizidine core. This methodology has been applied in the total syntheses of (+)-septicine, (+)-ipalbidine, and (+)-seco-antofine to illustrate the applicability of the general approach.

Viral hepatitis among acute hepatitis patients attending tertiary care hospital in central India.

Viral hepatitis is a considerable public health burden affecting millions of people throughout the world. The incidence of viral hepatitis varies greatly depending upon geographic locations, age and gender. Exploring the etiological spectrum and clinic-epidemiological profile of acute viral hepatitis (AVH) becomes essential for strategizing the preventive measures to control the diseases. An epidemiological data depicting AVH situation and its etiologies is missing from central India. With the aim of fulfilling this lacuna, the present analysis was done on samples tested over a period of 2 years from July 2015 to June 2017. Of the 1901 hepatitis cases, 597 individuals (31.4%) were positive for AVH infection and HEV was the predominant cause followed by HBV, HAV and HCV. Co-infections of hepatitis viruses were detected in 42 cases. Co-infection of HEV with HBV was the commonest pattern. Male preponderance was observed among AVH positive cases and the age group of 26-45 years was the most susceptible to the viral hepatitis infections, except hepatitis A, which was the most frequent among children. Two hundred patients (33.45%) required hospitalization and 51 deaths were attributed to AVH infections. The analysis for the first time reports intricacies and viral etiologies of AVH in central India. Regular diagnosis of AVH etiology and monitoring of cases will help in patient management and assist disease control programs to take policy decisions.

The NCATS Pharmaceutical Collection: a 10-year update.

The National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (NPC), a comprehensive collection of clinically approved drugs, was made a public resource in 2011. Over the past decade, the NPC has been systematically profiled for activity across an array of pathways and disease models, generating an unparalleled amount of data. These data have not only enabled the identification of new repurposing candidates with several in clinical trials, but also uncovered new biological insights into drug targets and disease mechanisms. This retrospective provides an update on the NPC in terms of both successes and lessons learned. We also report our efforts in bringing the NPC up-to-date with drugs approved in recent years.

Rapid prototyping technology for cranioplasty: A case series.

Cranial vault defects may be acquired or congenital in origin. Rehabilitation of these patients often poses challenge to the operating team and prosthodontist. Polymethylmethacrylate is a commonly used alloplastic graft material which is used for the fabrication of cranial prosthesis. Nowadays, with the advancement in the bioengineering, custom-made template and cranial prosthesis can be made by rapid prototyping technology (RPT) by patient three-dimensional (3D) computed tomography (CT) scan images. This series of two cases explained two different techniques for the rehabilitation of the patient with frontotemporoparietal cranial defect. Case 1 had a history of cerebrovascular accident, followed by decompression craniotomy which led to frontotemporoparietal defect of the left side. This defect area was associated with the cerebrospinal fluid accumulation which made delineation of underlying bony margins difficult and interfered with conventional impression procedures. Case 2 had a road traffic accident which led to intracerebral hemorrhage followed by decompression craniotomy which resulted in frontotemporoparietal defect of the right side. The patient had a poor neuromuscular control which impedes with the upright posture of the head during impression making of the defect area. Therefore, these cases were planned to rehabilitate by RPT. In these techniques, the prosthesis was made using custom-made skull template produced by RPT, using the data of 3D-CT scan images. This technique resulted in the prosthesis with good esthetics and better fit of the prosthesis. The contours of the prosthesis were replicated in the same manner as compared to the contralateral side. RPT is an additive manufacturing technology which is now used in the field of dentistry too. This technique is easy to use; fabricate prosthesis with high precision is less time-consuming and has fewer chances of error.

Fabrication of ocular prosthesis with a digital customization technique - A case report.

Loss of an eye can be caused by cancer, trauma, or congenital defects. A loss of eye creates functional, esthetic, and psychological lacunae in individual's personal and professional life. Rehabilitation of ocular defect can be done by a custom ocular prosthesis fabricated with heat cure polymethylmethacrylate. The custom-made prosthesis provides a better fit, is more comfortable to use and gives better cosmetic results than a stock prosthesis. The main objective of this article is to describe a new technique of customization using digital photograph of the patient's iris made using a digital camera to give excellent cosmetic results to the patient.

Pectin Methacrylate (PEMA) and Gelatin-Based Hydrogels for Cell Delivery: Converting Waste Materials into Biomaterials.

The emergence of nontoxic, eco-friendly, and biocompatible polymers derived from natural sources has added a new and exciting dimension to the development of low-cost and scalable biomaterials for tissue engineering applications. Here, we have developed a mechanically strong and durable hydrogel composed of an eco-friendly biopolymer that exists within the cell walls of fruits and plants. Its trade name is pectin, and it bears many similarities with natural polysaccharides in the native extracellular matrix. Specifically, we have employed a new pathway to transform pectin into a ultraviolet (UV)-cross-linkable pectin methacrylate (PEMA) polymer. To endow this hydrogel matrix with cell differentiation and cell spreading properties, we have also incorporated thiolated gelatin into the system. Notably, we were able to fine-tune the compressive modulus of this hydrogel in the range ∼0.5 to ∼24 kPa: advantageously, our results demonstrated that the hydrogels can support growth and viability for a wide range of three-dimensionally (3D) encapsulated cells that include muscle progenitor (C2C12), neural progenitor (PC12), and human mesenchymal stem cells (hMSCs). Our results also indicate that PEMA-gelatin-encapsulated hMSCs can facilitate the formation of bonelike apatite after 5 weeks in culture. Finally, we have demonstrated that PEMA-gelatin can yield micropatterned cell-laden 3D constructs through UV light-assisted lithography. The simplicity, scalability, processability, tunability, bioactivity, and low-cost features of this new hydrogel system highlight its potential as a stem cell carrier that is capable of bridging the gap between clinic and laboratory.

Blending Electronics with the Human Body: A Pathway toward a Cybernetic Future.

At the crossroads of chemistry, electronics, mechanical engineering, polymer science, biology, tissue engineering, computer science, and materials science, electrical devices are currently being engineered that blend directly within organs and tissues. These sophisticated devices are mediators, recorders, and stimulators of electricity with the capacity to monitor important electrophysiological events, replace disabled body parts, or even stimulate tissues to overcome their current limitations. They are therefore capable of leading humanity forward into the age of cyborgs, a time in which human biology can be hacked at will to yield beings with abilities beyond their natural capabilities. The resulting advances have been made possible by the emergence of conformal and soft electronic materials that can readily integrate with the curvilinear, dynamic, delicate, and flexible human body. This article discusses the recent rapid pace of development in the field of cybernetics with special emphasis on the important role that flexible and electrically active materials have played therein.

Combinatorial Screening of Nanoclay-Reinforced Hydrogels: A Glimpse of the "Holy Grail" in Orthopedic Stem Cell Therapy?

Despite the promise of hydrogel-based stem cell therapies in orthopedics, a significant need still exists for the development of injectable microenvironments capable of utilizing the  regenerative potential of donor cells. Indeed, the quest for biomaterials that can direct stem cells into bone without the need of external factors has been the "Holy Grail" in orthopedic stem cell therapy for decades. To address this challenge, we have utilized a combinatorial approach to screen over 63 nanoengineered hydrogels made from alginate, hyaluronic acid, and two-dimensional nanoclays. Out of these combinations, we have identified a biomaterial that can promote osteogenesis in the absence of well-established differentiation factors such as bone morphogenetic protein 2 (BMP2) or dexamethasone. Notably, in our "hit" formulations we observed a 36-fold increase in alkaline phosphate (ALP) activity and a 11-fold increase in the formation of mineralized matrix, compared to the control hydrogel. This induced osteogenesis was further supported by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy. Additionally, the Montmorillonite-reinforced hydrogels exhibited high osteointegration as evident from the relatively stronger adhesion to the bone explants as compared to the control. Overall, our results demonstrate the capability of combinatorial and nanoengineered biomaterials to induce bone regeneration through osteoinduction of stem cells in a natural and differentiation-factor-free environment.

Emerging Biofabrication Strategies for Engineering Complex Tissue Constructs.

The demand for organ transplantation and repair, coupled with a shortage of available donors, poses an urgent clinical need for the development of innovative treatment strategies for long-term repair and regeneration of injured or diseased tissues and organs. Bioengineering organs, by growing patient-derived cells in biomaterial scaffolds in the presence of pertinent physicochemical signals, provides a promising solution to meet this demand. However, recapitulating the structural and cytoarchitectural complexities of native tissues in vitro remains a significant challenge to be addressed. Through tremendous efforts over the past decade, several innovative biofabrication strategies have been developed to overcome these challenges. This review highlights recent work on emerging three-dimensional bioprinting and textile techniques, compares the advantages and shortcomings of these approaches, outlines the use of common biomaterials and advanced hybrid scaffolds, and describes several design considerations including the structural, physical, biological, and economical parameters that are crucial for the fabrication of functional, complex, engineered tissues. Finally, the applications of these biofabrication strategies in neural, skin, connective, and muscle tissue engineering are explored.