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Abstract: The prevalence of plant-based medicine has risen worldwide, not only as part of conventional treatment but also for health care management. The authenticity and quality of herbal medicines impact these medications' safety and effectiveness in clinical treatment. So, it is necessary to identify the chemical composition and quality of pharmacologically active ingredients in the plants as there is no pertinent data regarding the exact dose of the Herbal based medicine. Similarly, the Indian system of Medicine (ISM) based products may vary in composition and properties, and increasing reports of adverse reactions have drawn the attention of many regulatory agencies for the quality evaluation of traditional formulations. Moreover, ISM's quality control has always been an important domain, and its current quality standards have a complex effect to assure clinical efficacy. The Quality marker (Q-marker) technique is a new approach in Chinese traditional medicines to enhance and empower Chinese herbal drugs by focusing on each step of the plant processing from its growing phases to the marketed product formulation. The present review highlights the application of Q-marker and its tools for the establishment of quality standards of herbal drugs. Besides, this work also highlighted complies few Q-marker-based traditional Chinese medicines case studies. We expect that it would benefit the manufacturing process control and quality management of the Indian system of medicine. This work could provide a new direction for Q marker in the Indian system of medicine and contribute in the modernization and globalization of the Indian system of Medicine.

The application of stainless-steel wire is still the "standard of care" and is believed to be the "gold standard" after trans-sternal thoracotomy. To overcome postoperative instability and surgical wound infection there had been the development of a variety of circumferential, Hemi-circular, and surface on-lay implant designs to enhance bone healing of the sternum particularly in compromised patients. This fundamental descriptive theoretical research study probes into biology and effects of mechanical environment on fracture healing in general and various types of ossifications that may occur during healing of the sternum. Following surgical anatomy of the sternum, the biology of fracture (osteotomy) healing, an update on the conventional and newer biomaterials, and role of 3D printing in custom additive manufacturing of the surgical implants have been discussed in detail. There is discussion on design principles and structural optimization in-line with patient-specific and patient-appropriate osteosynthesis. In support, the Teorija Rezhenija Izobretatelskikh Zadatch engineering principles have been applied to improve implant design in the face of the current strategies to relieve some of the recalcitrant deficiencies underlying the mechanics of the most favored implant for the reconstruction of the sternum. Several scientific domains of the engineering design principles and fracture healing processes have been connected leading to four newly conceptualized prototype designs for the reconstruction of the sternum. In conclusion, despite increased knowledge of the fracture healing process there are limited means to mitigate the adverse mechanical environment experienced by the healing sternum. There are uncertainties how to transfer the well-known facts of tissue strain during healing from the experimental platform to the operating table at the time of fracture fixation and reconstruction of the sternum for its optimal healing.

Background: The procedure of minimal access to the brain through the nose is an ancient practice. However, endoscopic entry via a burr hole has recently gained significant traction in the practice of neurosurgery. High-resolution endoscopic images are possible with limited admittance of accessory tools and instruments. Although brain tissue can be removed easily with a suction device, but it will be uncontrolled ‘excision’. The Rotitome-G is a precision micro-endoscopic target access surgical instrument. It has several accessories for intraoperative assessment and precise removal of the soft tissue lesions pixel-by-pixel within a closed body cavity through a single portal. Objective: This preliminary theoretical research study on Rotitome-G is transition to experimental cadaveric and clinical studies. It describes the construction and mechanics of this newly conceptualized robot-assisted microsurgical endoscope. The design includes precise excision at the pixel and microscopic level and removes tissue debris under computer-aided navigation and direct instrument vision. Currently, the primary objective is to interest both the neurosurgeons and biomedical engineers, hence its contents are diverse resulting in an extended text. Methodology: The study provides the basics of computer vision techniques and neuronavigation to establish the function and application of the Rotitome-G. The structure and kinematics of the animalcule Rotifer have been considered followed by the construction of Rotitome-G. For a better understanding of intracranial tumour excision, the article examines the role of intra-operative imaging, biomechanics of brain tissue, and brain shift to better understand the principles of this newly conceived microsurgical instrument. The functional capabilities of the instrument have been putatively demonstrated by describing the excision of a glioblastoma. Conclusion: It is expected that the key design of Rotitome-G would meet the goal of neurosurgical resection by excising maximum amount of pathological tissue. Direct microscopic resection will prevent damage to the eloquent areas to improve the prognosis by limiting neurological morbidity. Clinical validity of the Rotitome -G remains to be determined.

Introduction: No two patients have similar normal anatomy and physiology because of genetics, physical development, and age that the same type of surgery and reconstruction implant will perform equally well. Such a notion demands the need for individualization of treatment and a method to select an ameliorative implant prospectively. One such empirically testing method is the finite element-n-of-1 (fe-n-of-1), where a treatment plan is executed specifically and systematically for a single patient as part of pre-operative planning. Objective: It is to evaluate and discuss the method of finite element analysis to carry out the fe-n-of-1 empirical test in a fact-driven manner connecting various scientific domains. It presents a preliminary protocol how to select an ameliorative implant to mitigate sternal instability due to suboptimal standard stainless-steel cerclage wiring to reconstruct the sternum following open-heart surgery. Methodology: The instability following the reconstruction of the sternum is a mechanical problem therefore it is appropriate to apply harmless structural engineering methods to choose a suitable implant design to fix it. This exploratory descriptive research describes finite element n-of-1 empirical testing using in-silico engineering principles applied to patient-specific and patient-appropriate mechanical loading conditions. Conclusion: Single-patient fe-n-of-1 empirical testing is a benign engineering method based on finite element modeling and finite element analysis. It is a safe mathematical evaluation free from subjective bias to select in advance the most ameliorative implant design to opt out of the suboptimal stainless steel cerclage wire as ‘standard of care’ and improve patient-based outcome and surgeon satisfaction.

Gingival recession associated with root surface exposure is a complex phenomenon that may present numerous therapeutic challenges to the clinician. Many patients seek treatment because of concerns about esthetic appearance, root sensitivity, or fear of early loss of the affected teeth. The most common cause for gingival recession is abrasive, traumatic tooth brushing habits and buccally positioned teeth. Multiple periodontal plastic surgery approaches are documented for the treatment of gingival recession defects. These treatment approaches generally includes the manipulation of patient tissues to augment the soft tissues and cover the exposed roots surfaces. The combination of sub epithelial connective tissue graft with a coronally positioned ap has been shown to demonstrate the highest success with predictable results.

Abstract: MicroRNAs (MiRNAs) are endogenous non-coding small RNA molecules that regulate gene expression in plants, animals and some viruses. Both normal and pathological liver processes are regulated by miRNAs. Recent research indicated that miRNAs have been implicated in liver diseases caused by viral hepatitis (Hepatitis B and Hepatitis C), metabolic problems, alcohol and drug abuse. Because altered miRNA expression is linked to liver metabolic dysregulation, liver damage, liver fibrosis, and tumour growth, miRNAs are promising therapeutic targets for the detection and treatment of liver diseases. In this review, we summarise the current knowledge about the role of microRNAs in acute and chronic liver diseases, including hepatocellular carcinoma. We cover the miRNA-based therapy for liver disorders as well as the use of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases. The investigation of miRNAs in liver diseases will provide a better understanding of the pathogeneses, identification of biomarkers and therapeutic targets for liver diseases in the future.

Table ST1: Glossary of terms used in the paper Figure S1. Genetic modification and expansion of CAR+ T cells. Figure S2. In vitro expansion of CAR+ T cells. Figure S3. High-throughput cytotoxicity assay for monitoring T-cell target cell interactions in nanowell grids. Figure S4. CD19 expression on NALM-6 tumor cells or CD19+EL4 target cells as determined by immunofluoresecent staining. Figure S5. Composite micrographs illustrating representative examples of the interactions between single CAR+ T cells (E) and one or more NALM-6 tumor (T) cells. Figure S6. Increased probability of killing by individual CAR+ T cells at higher target cell densities. Figure S7. Donut plots summarizing the outcomes of the interaction between individual CAR8 cells and 1-3 CD19+-NALM-6 tumor cells. Figure S8. Timelapse Imaging Microscopy In Nanowell Grids (TIMING). Figure S9. At an E:T ratio of 1:1, identification of subgroups of killer CAR8 cells based on their motility and contact behavior with tumor cells. Figure S10. At an E:T of 1:1, the total duration of conjugation prior to NALM-6 tumor cell killing is no different for the CAR8 cells in the different subgroups. Figure S11. At an E:T ratio of 1:1, CAR8 cells in the S1 subgroup, demonstrate: (A) drop in motility, and (B) increased circularization upon conjugation to NALM-6 tumor cell. Figure S12. At an E:T ratio of 1:1, CAR8 cells in the different subgroups demonstrate different frequencies and kinetics of AICD subsequent to the interactions with NALM-6 cells. Figure S13. At an E:T ratio of 1:2-5, multi-killer CAR8 cells demonstrate no significant differences in their duration of conjugation prior to killing multiple NALM-6 tumor cells. Figure S14. Despite the increased crowding because of higher tumor cell density, multi-killer CAR8 cells displayed greater motility when conjugated to tumor cell in comparison to single-killer CAR8 cells that encountered only a single tumor cell. Figure S15. At an E:T ratio of 1:1, identification of subgroups of killer CAR4 cells based on their motility and contact behavior with tumor cells. Figure S16. At an E:T of 1:1, the total duration of conjugation prior to NALM-6 tumor cell killing is significantly longer for CAR4 cells in S2 subgroup in comparison to subgroups S1 and S3. Figure S17. At an E:T of 1:1, CAR4 cells in S2 subgroup induce apoptosis in tumor cells with delayed kinetics in comparison to CAR8 cells in the S2 subgroup. Figure S18. At an E:T ratio of 1:2-5, multi-killer CAR4 cells demonstrate increased circularization upon contact with one or more NALM-6 tumor cells. Figure S19. The ability of individual CAR4 cells to simultaneously conjugate to multiple NALM-6 tumor cells increases as the number of tumor cells within the nanowell increases. Figure S20. Comparison of the killing efficiency of individual single killer CAR+ T cells (E:T 1:1) with multi-killer CAR+ T cells (E:T 1:2-5) that killed multiple NALM-6 tumor cells.

T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy in Nanowell Grids (TIMING) to provide direct evidence that CD4+CAR+ T cells (CAR4 cells) can engage in multikilling via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8+CAR+ T cells (CAR8 cells) demonstrate that, although CAR4 cells can participate in killing and multikilling, they do so at slower rates, likely due to the lower granzyme B content. Significantly, in both sets of T cells, a minor subpopulation of individual T cells identified by their high motility demonstrated efficient killing of single tumor cells. A comparison of the multikiller and single-killer CAR+ T cells revealed that the propensity and kinetics of T-cell apoptosis were modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation, and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR+ T cells to participate in multikilling should be evaluated in the context of their ability to resist activation-induced cell death. We anticipate that TIMING may be used to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR+ T cells with improved efficacy. Cancer Immunol Res; 3(5); 473–82. ©2015 AACR.See related commentary by June, p. 470

Movie M4. Representative example of a CAR8 cell that kills multiple tumor cells.

Movie M1. Representative example of a CAR8 cell from the S1 subgroup.

Movie M2. Representative example of a CAR8 cell from the S2 subgroup.

Movie M3. Representative example of a CAR8 cell from the S3 subgroup.

Movie M5. Representative example of a CAR4 cell that kills multiple tumor cells.

Tables 1 and 2. Table 1: List of antibodies used in this study. Table 2: List of mRNA sequences assessed by digital molecular barcoding using the nCounter

Supplementary Video C. VTLM single cell killing of HEK293 cells by HERV-K env-specific CAR+ T cells

Purpose: The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T-cell surface, such that they target tumors in advanced stages of melanoma.Experimental Design: Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immunohistochemical (IHC) analysis. HERV-K env–specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env–specific CAR+ T cells were expanded ex vivo on activating and propagating cells (AaPC) and characterized for CAR expression and specificity. This includes evaluating the HERV-K–specific CAR+ T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model.Results: We detected HERV-K env protein on melanoma but not in normal tissues. After electroporation of T cells and selection on HERV-K+ AaPC, more than 95% of genetically modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env+ tumor targets in an antigen-specific manner. Even though there is apparent shedding of this TAA from tumor cells that can be recognized by HERV-K env–specific CAR+ T cells, we observed a significant antitumor effect.Conclusions: Adoptive cellular immunotherapy with HERV-K env–specific CAR+ T cells represents a clinically appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors. Clin Cancer Res; 21(14); 3241–51. ©2015 AACR.

Supplementary Video D. Physical health of mice group with tumor and without HERV-K env-specific CAR+ T-cell treatment.

Supplementary figure 3 and 4. Figure S3: Generation and specificity of 6H5mAx. Figure. S4: Generation of EL4-HERV-K and specificity of HERV-K env-specific CAR+ T cells.

Supplementary materials

Supplementary figure 1 and 2. Figure S1: HERV-K env expression on primary tumor and normal human tissues. Figure. S2: Phenotype and mRNA profile of HERV-K env-specific CAR+ T cells.

Supplementary figure 5. Generation and specificity of HERV-K env-specific CAR+ ffLuc+ T cells in vitro and in vivo.

Supplementary Video E. Physical health of mice group with tumor and with HERV-K env-specific CAR+ T-cell treatment.

Supplementary Figure 1 from Reprogramming CD19-Specific T Cells with IL-21 Signaling Can Improve Adoptive Immunotherapy of B-Lineage Malignancies

Supplementary Materials and Methods

Activation and functional response of Cetux-CAR+ and Nimo-CAR+ T cells in response to cell lines with varying endogenous EGFR expression

Antibodies used in study

Supplementary Video 2 from Combining Adoptive Cellular and Immunocytokine Therapies to Improve Treatment of B-Lineage Malignancy

Supplementary Video 1 from Combining Adoptive Cellular and Immunocytokine Therapies to Improve Treatment of B-Lineage Malignancy

Engraftment of intracranial tumor and CAR+ T-cell phenotype prior to administration of T cells

Currently, the lineage-specific cell-surface molecules CD19 and CD20 present on many B-cell malignancies are targets for both antibody- and cell-based therapies. Coupling these two treatment modalities is predicted to improve the antitumor effect, particularly for tumors resistant to single-agent biotherapies. This can be shown using an immunocytokine, composed of a CD20-specific monoclonal antibody fused to biologically active interleukin 2 (IL-2), combined with ex vivo expanded human umbilical cord blood–derived CD8+ T cells, that have been genetically modified to be CD19 specific, for adoptive transfer after allogeneic hematopoietic stem-cell transplantation. We show that a benefit of targeted delivery of recombinant IL-2 by the immunocytokine to the CD19+CD20+ tumor microenvironment is improved in vivo persistence of the CD19-specific T cells, and this results in an augmented cell-mediated antitumor effect. Phase I trials are under way using anti-CD20-IL-2 immunocytokine and CD19-specific T cells as monotherapies, and our results warrant clinical trials using combination of these two immunotherapies. [Cancer Res 2007;67(6):2872–80]

Production of TNF-a by Cetux-CAR and Nimo-CAR+ T cells in response to different densities of EGFR

Ratio of CD4 and CD8 on Cetux-CAR+ and Nimo-CAR+ T cells

Surface expression of CAR during co-culture with tEGFR+ EL4 or CAR-L+ EL4

Schematic of plasmids and AaPC

Video 1A case of recurrence after Z-POEM because of incomplete myotomy on the esophageal side.

Introduction: The endeavour to improve medical image segmentation techniques for higher analysis in surgical planning and medical therapeutics is far from becoming a standard of care in clinical practice. Hyalite Sol-Gel Amoeba model based on biophysical sciences apart from performing image segmentation is designed to extract real-world tissue densities for patient-specific and patient-appropriate analysis. Objectives: Amoeba Proteus is a unicellular independent entity, with a nucleus and sol-gel protoplasm enclosed in a membrane. The study presents versatile restructuring anatomy and physiology of the Amoeba Proteus for segmentation of 2D, and 3D medical images based on well-established principles of energy minimization and active contour. It demonstrates how the animalcule glides and advances by throwing pseudopodia driven by phenomenal actin-myosin activity that can segment a region-of-interest, and finally, at the time of apoptosis, its protoplasm and organelles acquire distribution of original image intensities to characterize tissue densities. Methods: This seminal study following a brief review of computer vision science discusses the relationship between optical density and tissue density, and the theory of sol-gel fluid mechanics. The framework of the HSG-Amoeba is described with the segmentation of various skeletal components of the thoracic cage. Results: This being a foundational study to describe the concept of the HSG-Amoeba model it requires the development of a mathematical algorithm to demonstrate its worthiness as a tool for surgical applications. Conclusion: The focus of the study is to present the design and framework of the newly conceived HSG-Amoeba model to segment a medical image and extract tissue densities without altering the original image intensities.

In recent years deep learning models are very popular for image classification. Convolution Neural Networks (CNNs) are commonly used for image classification and based on the architecture of these models there are various transfer learning models which are pre-trained on the ImageNet dataset. The accuracy of these models depends upon the various parameters, such as the number of layers, kernel size, image size, etc. In the current study, we analyze the effect of kernel size on the CNNs model for image classification. We consider the CGIAR wheat rust disease image dataset for experimentation. After performing various experiments, it is found that using a small kernel size leads to the reduction of several parameters of the model and also has a significant effect on the accuracy of the model.