Inflammatory Components of the Thyroid Cancer Microenvironment: An Avenue for Identification of Novel Biomarkers.

The incidence of thyroid cancer in the United States is on the rise with an appreciably high disease recurrence rate of 20-30%. Anaplastic thyroid cancer (ATC), although rare in occurrence, is an aggressive form of cancer with limited treatment options and bleak cure rates. This chapter uses discussions of in vitro models that are representative of papillary, anaplastic, and follicular thyroid cancer to evaluate the crosstalk between specific cells of the tumor microenvironment (TME), which serves as a highly heterogeneous realm of signaling cascades and metabolism that are associated with tumorigenesis. The cellular constituents of the TME carry out varying characteristic immunomodulatory functions that are discussed throughout this chapter. The aforementioned cell types include cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs), as well as specific immune cells, including natural killer (NK) cells, dendritic cells (DCs), mast cells, T regulatory (Treg) cells, CD8+ T cells, and tumor-associated macrophages (TAMs). TAM-mediated inflammation is associated with a poor prognosis of thyroid cancer, and the molecular basis of the cellular crosstalk between macrophages and thyroid cancer cells with respect to inducing a metastatic phenotype is not yet known. The dynamic nature of the physiological transition to pathological metastatic phenotypes when establishing the TME encompasses a wide range of characteristics that are further explored within this chapter, including the roles of somatic mutations and epigenetic alterations that drive the genetic heterogeneity of cancer cells, allowing for selective advantages that aid in their proliferation. Induction of these proliferating cells is typically accomplished through inflammatory induction, whereby chronic inflammation sets up a constant physiological state of inflammatory cell recruitment. The secretions of these inflammatory cells can alter the genetic makeup of proliferating cells, which can in turn, promote tumor growth.This chapter also presents an in-depth analysis of molecular interactions within the TME, including secretory cytokines and exosomes. Since the exosomal cargo of a cell is a reflection and fingerprint of the originating parental cells, the profiling of exosomal miRNA derived from thyroid cancer cells and macrophages in the TME may serve as an important step in biomarker discovery. Identification of a distinct set of tumor suppressive miRNAs downregulated in ATC-secreted exosomes indicates their role in the regulation of tumor suppressive genes that may increase the metastatic propensity of ATC. Additionally, the high expression of pro-inflammatory cytokines in studies looking at thyroid cancer and activated macrophage conditioned media suggests the existence of an inflammatory TME in thyroid cancer. New findings are suggestive of the presence of a metastatic niche in ATC tissues that is influenced by thyroid tumor microenvironment secretome-induced epithelial to mesenchymal transition (EMT), mediated by a reciprocal interaction between the pro-inflammatory M1 macrophages and the thyroid cancer cells. Thus, targeting the metastatic thyroid carcinoma microenvironment could offer potential therapeutic benefits and should be explored further in preclinical and translational models of human metastatic thyroid cancer.

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense.

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb-neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.

The novel gene apnoia regulates Drosophila tracheal tube size.

BACKGROUND: Distinct tube size is critical for the function of human tubular organs such as the lung, vascular system, and kidney. Aberrant tube sizes can lead to devastating human illnesses, including polycystic kidney disease. The Drosophila trachea provides a premier genetic system to investigate the fundamental mechanisms that regulate tube size. RESULTS: Here we describe the function of a novel gene, apnoia, in tube-size regulation. apn encodes an apical membrane protein, Apnoia (Apn), with three helical transmembrane domains. Loss-of-function apn mutants show shorter-tube and air-filling defects in larval trachea, whereas there are no obvious defects in embryonic trachea. Conversely, overexpression of apn in trachea leads to significant tube over-elongation. We analyzed apical luminal matrix and cell polarity in these longer tubes. It is interesting to note that we observed normal establishment of cell polarity, whereas all luminal matrix components are significantly reduced. In addition, we observed that some matrix components are localized in cytoplasmic vesicles, suggesting secretion defects in apn overexpressing trachea. CONCLUSION: Taken together, these results strongly suggest the possibility that apn is directly or indirectly involved in vesicular trafficking to regulate tube size.

Protective effect of Salacia oblonga against tobacco smoke-induced DNA damage and cellular changes in pancreatic ß-cells.

CONTEXT: Tobacco smoking generates a tremendous amount of free radicals that induce oxidative stress (OS) in diabetics (pancreatic islet cells are defective). Salacia oblonga Wall. (Celastraceae) is a proven antioxidant and antidiabetic plant whose mechanism of action is yet to be explored. OBJECTIVE: The present study focuses on the protective ability of S. oblonga in tobacco smoke-induced oxidatively stressed pancreatic ß-cell line. MATERIALS AND METHODS: The RINm5f cell line was exposed to tobacco smoke concentrate (TSC) (0.5-10%, 24 h), plant extract (1-75 µg/ml, 3 h), and their combinations. Cell viability was determined through MTT assay. Microscopic analysis was carried out in unstained and nonyl acridine orange-stained cells. The effect of toxic doses of TSC on DNA integrity was analyzed through DNA fragmentation assay. The TSC-induced nitric oxide generation was determined spectrophototmetrically. The expression of anti-apoptotic protein Bcl-X under the above treatment conditions was carried out through RT-PCR. RESULTS: The LD50 dose for TSC was found to be 1% TSC. Salacia oblonga extracts (10 and 15 µg/ml) were found to be optimum safe doses that significantly increased cell viability and decreased the nitric oxide production in TSC-treated cells. Pre-treatment with plant extract suppressed apoptosis through probable increase in the expression of anti-apoptotic protein Bcl-X in TSC-treated cells. Thus, the overall efficiency of plant extract in recovering cellular damage was proven. DISCUSSION AND CONCLUSION: The results suggest that TSC-induced cellular alterations are related to rise in nitric oxide and Bcl-X mRNA expression and propose that S. oblonga may confer significant cytoprotection against OS-mediated injury in ß-cells.

The novel Smad protein Expansion regulates the receptor tyrosine kinase pathway to control Drosophila tracheal tube size.

Tubes with distinct shapes and sizes are critical for the proper function of many tubular organs. Here we describe a unique phenotype caused by the loss of a novel, evolutionarily-conserved, Drosophila Smad-like protein, Expansion. In expansion mutants, unicellular and intracellular tracheal branches develop bubble-like cysts with enlarged apical membranes. Cysts in unicellular tubes are enlargements of the apical lumen, whereas cysts in intracellular tubes are cytoplasmic vacuole-like compartments. The cyst phenotype in expansion mutants is similar to, but weaker than, that observed in double mutants of Drosophila type III receptor tyrosine phosphatases (RPTPs), Ptp4E and Ptp10D. Ptp4E and Ptp10D negatively regulate the receptor tyrosine kinase (RTK) pathways, especially epithelial growth factor receptor (EGFR) and fibroblast growth factor receptor/breathless (FGFR, Btl) signaling to maintain the proper size of unicellular and intracellular tubes. We show Exp genetically interacts with RTK signaling, the downstream targets of RPTPs. Cyst size and number in expansion mutants is enhanced by increased RTK signaling and suppressed by reduced RTK signaling. Genetic interaction studies strongly suggest that Exp negatively regulates RTK (EGFR, Btl) signaling to ensure proper tube sizes. Smad proteins generally function as intermediate components of the transforming growth factor-ß (TGF-ß, DPP) signaling pathway. However, no obvious genetic interaction between expansion and TGF-ß (DPP) signaling was observed. Therefore, Expansion does not function as a typical Smad protein. The expansion phenotype demonstrates a novel role for Smad-like proteins in epithelial tube formation.

A new species of the genus Scirtothrips (Thysanoptera, Thripidae) from India.

A new species of Scirtothrips is described from India, S. donumdei, collected on leaves of Senegalia pennata (Fabaceae). Partial mitochondrial cytochrome c oxidase subunit 1 (mtCOI) gene sequence of the species was sequenced and the annotated sequence was submitted to NCBI GenBank.

Dedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease.

Alveolarization ensures sufficient lung surface area for gas exchange, and during bulk alveolarization in mice (postnatal day [P] 4.5-14.5), alpha-smooth muscle actin (SMA)+ myofibroblasts accumulate, secrete elastin, and lay down alveolar septum. Herein, we delineate the dynamics of the lineage of early postnatal SMA+ myofibroblasts during and after bulk alveolarization and in response to lung injury. SMA+ lung myofibroblasts first appear at ∼ P2.5 and proliferate robustly. Lineage tracing shows that, at P14.5 and over the next few days, the vast majority of SMA+ myofibroblasts downregulate smooth muscle cell markers and undergo apoptosis. Of note, ∼8% of these dedifferentiated cells and another ∼1% of SMA+ myofibroblasts persist to adulthood. Single cell RNA sequencing analysis of the persistent SMA- cells and SMA+ myofibroblasts in the adult lung reveals distinct gene expression profiles. For instance, dedifferentiated SMA- cells exhibit higher levels of tissue remodeling genes. Most interestingly, these dedifferentiated early postnatal myofibroblasts re-express SMA upon exposure of the adult lung to hypoxia or the pro-fibrotic drug bleomycin. However, unlike during alveolarization, these cells that re-express SMA do not proliferate with hypoxia. In sum, dedifferentiated early postnatal myofibroblasts are a previously undescribed cell type in the adult lung and redifferentiate in response to injury.

Loss of cell junctional components and matrix alterations drive cell desquamation and fibrotic changes in Idiopathic Pulmonary Fibrosis.

The distal bronchioles in Idiopathic Pulmonary Fibrosis (IPF) exhibit histopathological abnormalities such as bronchiolization, peribronchiolar fibrosis and honeycomb cysts that contribute to the overall architectural remodeling of lung tissue seen in the disease. Here we describe an additional histopathologic finding of epithelial desquamation in patients with IPF, wherein epithelial cells detach from the basement membrane of the distal bronchioles. To understand the mechanism driving this pathology, we performed spatial transcriptomics of the epithelial cells and spatial proteomics of the basement membrane of the distal bronchioles from IPF patients and patients with no prior history of lung disease. Our findings reveal a downregulation of cell junctional components, upregulation of epithelial-mesenchymal transition signatures and dysregulated basement membrane matrix in IPF distal bronchioles, facilitating epithelial desquamation. Further, functional assays identified regulation between Collagen IV in the matrix, and the junctional genes JUP and PLEC , that is crucial for maintaining distal bronchiolar homeostasis. In IPF, this balanced regulation between matrix and cell-junctions is disrupted, leading to loss of epithelial adhesion, peribronchiolar fibrosis and epithelial desquamation. Overall, our study suggests that in IPF the interplay between the loss of cell junctions and a dysregulated matrix results in desquamation of distal bronchiolar epithelium and lung remodeling, exacerbating the disease. One Sentence Summary: Two-way regulation of cell junctional proteins and matrix proteins drives cellular desquamation and fibrosis in the distal bronchioles of patients with Idiopathic Pulmonary Fibrosis.

Novel mechanisms of tube-size regulation revealed by the Drosophila trachea.

The size of various tubes within tubular organs such as the lung, vascular system and kidney must be finely tuned for the optimal delivery of gases, nutrients, waste and cells within the entire organism. Aberrant tube sizes lead to devastating human illnesses, such as polycystic kidney disease, fibrocystic breast disease, pancreatic cystic neoplasm and thyroid nodules. However, the underlying mechanisms that are responsible for tube-size regulation have yet to be fully understood. Therefore, no effective treatments are available for disorders caused by tube-size defects. Recently, the Drosophila tracheal system has emerged as an excellent in vivo model to explore the fundamental mechanisms of tube-size regulation. Here, we discuss the role of the apical luminal matrix, cell polarity and signaling pathways in regulating tube size in Drosophila trachea. Previous studies of the Drosophila tracheal system have provided general insights into epithelial tube morphogenesis. Mechanisms that regulate tube size in Drosophila trachea could be well conserved in mammalian tubular organs. This knowledge should greatly aid our understanding of tubular organogenesis in vertebrates and potentially lead to new avenues for the treatment of human disease caused by tube-size defects.

A new species of Hydatothrips (Thysanoptera, Thripidae) from India with one new record.

A remarkable new species, Hydatothrips longirostris, with an elongate mouth cone extending to the metasternum is described from India. Dendrothrips glynn Mound, a dendrothripine species, is newly recorded from India.

Anatomical Variations of the Greater Palatine Foramen in Different Facial Skeletal Relationships and its Implications on LeFort 1 Osteotomy (Trimble's Modification).

Purpose: To determine the positional variations of the greater palatine foramen in different facial skeletal relationships and discuss its surgical implications on the Trimble's modification of Lefort I osteotomy. Materials and Methods: This retrospective study examined 50 computed tomography scans of patients a total of 100 sides. The sample was divided into four groups: Class 1, Class 2, Class 3 malocclusion and Unilateral cleft lip and palate). The outcome variables included the distance between anterior, middle and posterior points of the GPF to the distal of second molar and variables to assess relative position of the GPF to the posterior maxilla. Outcome measures were to demonstrate intra- and intergroup variability. Results: Fifty patients (100 sides) were divided into four groups. This included 23 males and 27 females with a mean age of 24.1 years. Significant intergroup variability was observed between all the parameters that demonstrate the relative position of the GPF to (i) the maxillary second molar and (ii) the posterior maxilla. The analysis revealed that the GPF was positioned significantly anterior in Class 2 patients when compared with Class 3 patients. Conclusion: The GPF exhibits significant positional variability in different facial skeletal relationships which should be borne in mind while designing and performing the Trimble's modification of the Lefort 1 osteotomy.

Amyotrophic Lateral Sclerosis Risk Genes and Suppressor.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to death by progressive paralysis and respiratory failure within 2-4 years of onset. About 90-95% of ALS cases are sporadic (sALS), and 5-10% are inherited through family (fALS). Though the mechanisms of the disease are still poorly understood, so far, approximately 40 genes have been reported as ALS causative genes. The mutations in some crucial genes, like SOD1, C9ORF72, FUS, and TDP-43, are majorly associated with ALS, resulting in ROS-associated oxidative stress, excitotoxicity, protein aggregation, altered RNA processing, axonal and vesicular trafficking dysregulation, and mitochondrial dysfunction. Recent studies show that dysfunctional cellular pathways get restored as a result of the repair of a single pathway in ALS. In this review article, our aim is to identify putative targets for therapeutic development and the importance of a single suppressor to reduce multiple symptoms by focusing on important mutations and the phenotypic suppressors of dysfunctional cellular pathways in crucial genes as reported by other studies.

Corticomuscular Coherence in Children with Unilateral Cerebral Palsy: A Feasibility and Preliminary Protocol Study.

Objective This study assessed the feasibility of corticomuscular coherence measurement during a goal-directed task in children with unilateral cerebral palsy while establishing optimal experimental parameters. Methods Participants (Manual Ability Classification System levels I-III) completed a submaximal isometric goal-directed grip task during simultaneous electroencephalography and electromyography (EMG) acquisition. Results All participants (n = 11, 6 females, mean age 11.3 ±2.4 years) completed corticomuscular coherence procedures. Of the 40 trials obtained per extremity, an average of 29 (n = 9) and 27 (n = 10) trials were retained from the more- and less-affected extremities, respectively. Obtaining measurement stability required an average of 28 trials per extremity. Conclusion Findings from this work support the feasibility of corticomuscular coherence measurement in children with unilateral cerebral palsy. Acquiring 28 to 40 corticomuscular coherence trials per extremity is ideal. The experimental parameters established in this work will inform future corticomuscular coherence application in pediatric unilateral cerebral palsy.

The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques.

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to ~70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin ß3 resulting in increased tumor necrosis factor [TNF]-α signaling. TNFα signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin ß3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies.

The Sericothripinae genus Hydatothrips (Thysanoptera, Thripidae) in India with description of a new species.

A new species of Hydatothrips is described from India, H. initium. A key to the ten species of Hydatothrips recorded from India is also provided.

Studies on Pseudodendrothrips (Thysanoptera, Thripidae) from India, with one new species.

Pseudodendrothrips umbrolateralis sp. n. is described from India. An identification key to the seven Pseudodendrothrips species recorded from India is provided. The earlier record from India of P. bhattii Kudo is considered a misidentification of P. darci (Girault) and hence, is removed from the fauna of India.

Recent adventive soft scale insects (Hemiptera: Coccomorpha: Coccidae) and mealybugs (Hemiptera: Coccomorpha: Pseudococcidae) in India.

Four species of soft scale insect [Hemiptera: Coccidae: Fistulococcus pokfulamensis Hodgson & Martin, Kilifia deltoides De Lotto, Maacoccus piperis (Green) and Paralecanium machili Takahashi] and two species of mealybug [Hemiptera: Pseudococcidae: Antonina thaiensis Takahashi and Formicococcus simplicior (Green)] are recorded in India for the first time. Each of the six species is comprehensively diagnosed based on Indian material, and compared with earlier descriptions. Keys to the Indian species in their respective genera are provided to facilitate identification. Ecological information on host plants, associated ants and natural enemies is also given.

Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.

GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.

A new species of Neohydatothrips (Thysanoptera: Thripidae) from India.

With 120 described species (ThripsWiki 2020) Neohydatothrips is the most species-rich genus in the Thripidae subfamily Sericothripinae. Although widely distributed almost 70% of the species are from the New World (Lima Mound 2016), with only seven species recorded from India (Rachana Varatharajan 2017). The biology of most species in the genus remains unknown, but they apparently feed and breed on the leaves and/or flowers of various unrelated plants. A few species are economically important as plant pests as well as virus vectors, such as N. variabilis (Beach) (Zhou Tzanetakis 2013; Lima Mound 2016; Han et al. 2019). N. samayunkur (Kudo) is a pest on flowers and leaves of Tagetes spp. in many countries including India (Nakahara 1999; Bhatti et al. 2003). Even though N. gracilipes (Hood) was described originally as damaging cotton in Mexico, it is associated with weedy species of Sida in several countries including central India (Lima Mound 2016). In southern China, N. flavicingulus Mirab-balou, Tong Yang is reported as damaging leaves of Manglietia fordiana. In California, avocado crops are sometimes damaged by N. burungae (Hood) and this species is also recorded as distorting the young leaves of Passiflora in Colombia (Mound et al. 2019). N. gracilicornis (Williams) is reported as damaging Pinaceae and Betulaceae in Spain and South Italy (Marullo 2009). The purpose of this article is to describe a new species from India that was collected in the flowers of Jasminum sambac (Oleaceae) in Assam, northeastern India. A detailed structural diagnosis of this genus is provided by Masumoto and Okajima (2020).

Safety and immunogenicity of rabies vaccine as 4 - dose Essen Intramuscular regimen for post exposure prophylaxis: A non - randomized, comparative controlled study.

Introduction: World Health Organization has recommended that in healthy persons with category III exposures, who receive wound care and rabies immunoglobulin infiltration, a vaccine regimen consisting of 4 doses administered intramuscularly on days 0, 3, 7, and 14 can be used as an alternative to the 5-dose intramuscular regimen.Objective: To assess the clinical safety and immunogenicity of rabies vaccine administered as 4-dose Essen intramuscular regimen for post-exposure prophylaxis.Methods: A non-randomized, comparative, controlled study was conducted at the anti-rabies clinic, KIMS Hospital and Research Center, Bangalore, India. The study subjects were divided into study group i.e., 4-dose intramuscular regimen, and control group i.e., 5-dose intramuscular regimen, and were given post-exposure prophylaxis. All subjects were followed for any adverse drug events. Rabies virus neutralizing antibodies was determined on day 14, 90 & 180 at the WHO collaborating center, NIMHANS, Bangalore, India to assess the immunogenicity.Results: The present study included 70 adult animal bite victims, 35 each in study group and control group. The incidence of ADEs was 7.8% in 4-dose Essen group and 7.0% in 5-dose Essen group;the difference between them was not significant (P > .05). Similarly, all the subjects in both the groups had protective antibody titers of ≥ 0.5 IU/mL (100% seroprotective) from day 14 till day 180; the difference between two groups was also not significant (P > .05).Conclusion: The 4-dose intramuscular Essen post-exposure prophylaxis regimen was found to be clinically safe and immunogenic.