Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications

Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year, despite best available treatment including radiotherapy (RT). Impacts of prior brain RT on recurrent tumors are poorly understood, though increasing evidence suggests RT-induced changes in the brain microenvironment contribute to recurrent GBM aggressiveness. The tumor microenvironment impacts malignant cells directly and indirectly through stromal cells that support tumor growth. Changes in extracellular matrix (ECM), abnormal vasculature, hypoxia, and inflammation have been reported to promote tumor aggressiveness that could be exacerbated by prior RT. Prior radiation may have long-term impacts on microglia and brain-infiltrating monocytes, leading to lasting alterations in cytokine signaling and ECM. Tumor-promoting CNS injury responses are recapitulated in the tumor microenvironment and augmented following prior radiation, impacting cell phenotype, proliferation, and infiltration in the CNS. Since RT is vital to GBM management, but substantially alters the tumor microenvironment, we here review challenges, knowledge gaps, and therapeutic opportunities relevant to targeting pro-tumorigenic features of the GBM microenvironment. We suggest that insights from RT-induced changes in the tumor microenvironment may provide opportunities to target mechanisms, such as cellular senescence, that may promote GBM aggressiveness amplified in previously radiated microenvironment

Preta grahonmada - Catatonia?

Unmada (a broad clinical entity which includes various psychiatric problems) is a major psychiatric condition described in Ayurvedic classics, and it is characterized by deranged mental functions. Unmaada is classified into two groups, doshajaunmaada (occurs due to vitiation of humors inside the body) and bhutonmaada or grahonmaada (not related to vitiation of humors and not caused by the factors inside the body). Bhootonmada is caused by the affliction of evil spirits or supernatural powers or extraterrestrial forces. Preta grahonmada (PG) is one among 18 types (deva, asura, rushi, guru, vruddha, siddha, pitru, gandharva, yaksha, rakshasa, sarpa, brahma rakshasa, pishacha, kushmanda, nishada, preta, maukirana, and vetala) of grahonmada. Till date, no studies have been conducted on PG, and the present study aims at better understanding of PG along with its clinical utility. PG is characterized by Pretakriti, cheshta, and gandha (appearance, behavior/activities and emitting odor-like dead body), Trinacchedinam (purposeless activities), Bheetam (fear or anxiety), and Aahaaradveshinam (aversion to food). Catatonia is a complex neuropsychiatric syndrome characterized by a broad range of motor, speech, and behavioral abnormalities. “Waxy flexibility,” “posturing,” and “catalepsy” are among the well-recognized motor abnormalities associated with catatonia. Catatonia is characterized by the features such as stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerisms, stereotypy, agitation, grimacing, echolalia, and echopraxia. Other common symptoms are motor resistance to simple commands, posturing, rigidity, automatic obedience, and repetitive movements. The features of PG have shown similarity with “Catatonia.” There is profound similarity found between PG and Catatonia

Maukirana grahonmada – Psychiatric manifestations of Graves' hyperthyroidism and ophthalmopathy?

Bhuta vidya (Ayurvedic psychiatry) is one of the eight specialties of Ayurveda. It deals with various psychiatric conditions caused by the affliction of evil spirits. Unmada (a broad term which consists various psychiatric problems) is a major psychiatric condition described in Ayurvedic and it is characterized by deranged mental functions. “Bhutonmada” (psychiatric conditions of idiopathic nature) is a type of unmada caused by the affliction of “bhoota”/“graha” (evil spirits or supernatural powers). Maukirana grahonmada (MG) is one among 18 types (deva, asura, rushi, guru, vruddha, siddha, pitru, gandharva, yaksha, rakshasa, sarpa, brahma rakshasa, pishacha, kushmanda, nishada, preta, maukirana, and vetala) of bhutonmada. Till date, there were no studies available on MG and the present study aims at better understanding along with clinical applicability of MG. MG is characterized by Ugravaadinam (agitation/aggression/verbal abuse), Rakta, trasta netram (reddish and tired eyes), Yaachantam annam (begging food), and Yaachantam udakarm (begging water). It is very difficult to understand MG based on these few lakshana's (signs and symptoms). Graves' disease (GD) (hyperthyroidism) with ophthalmopathy has shown similarity with MG. GD associated with hyperthyroidism and ophthalmopathy has shown marked similarity with MG. MG is having similarity with GD and Graves' ophthalmopathy

Uraga grahonmada: Extrapyramidal movement disorder?/Tourette syndrome-plus?

Uraga/Sarpa/Bhujaga grahonmada (UG) is one among the 18 types of bhootonmada. Bhootonmada denotes a category of psychiatric/neuropsychiatric conditions assumed to be caused by affliction of evil spirits (bhuta/graha). Till date, no studies have been conducted on UG and it is unexplored. The present study is focused on the better understanding of UG and its clinical applicability. UG is characterized by features of Krodhanam (aggressiveness/impulsivity), Nishwasantam (hyperventilation/anxiety/phobia), Bhramantam (agitation/restlessness/hyperactivity), Trasyantam (startle response/hyperekplexia/anxiety/phobia), Raktaaksha (red eyes/Kayser–Fleischer rings), Stabdha drishtim (prolonged staring/abnormal eye movements), Jihwa lolayantam/Srikkinyau lihaan (facial tics), Sarpavat prasarati/Adhomukha shaayinam (athetosis/chorea/motor tics/opisthotonus), Chalam/Vakra gamanam (gait abnormalities), Ksheera, ghrita, guda, and madhu priyam (craving for sweets), Snaana maalya priyam (obsessive-compulsive features), Gaatraani kampayantam (tremors/motor tics/seizures), Dantai khaadantam (self-injurious behaviors/oromandibular dystonia/bruxism), Nidraalu (hypersomnia/excessive daytime sleepiness), etc.. The clinical picture of UG shows similarity with various “extrapyramidal movement disorders” and also with “Tourette syndrome-plus.

Kleine − Levin syndrome: An ayurvedic perspective

Kleine − Levin syndrome (KLS), also known as sleeping beauty syndrome, is characterized by the classic triad of hypersomnia, hyperphagia, and hypersexuality. It is an intriguing and severe disease with no clear etiology or management. The present study aims for better understanding of KLS according to Ayurveda and to propose an Ayurvedic management protocol for it. The present study has explored the similarity between KLS and an Ayurvedic diagnostic entity, Bhutonmada, or Grahonmada. Bhutonmada is the most suitable provisional diagnosis for the patients of primary KLS. Yaksha Grahonmada is the most perfect match for KLS though some of the clinical features are dissimilar. Bhutonmada Chikitsa as explained in Ayurvedic texts could be implemented to manage KLS. Panchakarma (Ayurvedic detoxification) procedures, Daiva Vyapashraya Chikitsa, Sattvavajaya Chikitsa, Achara Rasayana along with medications may play an important role in the management of KLS. Hypersomina episodes of KLS could be managed with Ati Nidra Chikitsa. The present work provides new insights and also paves the path for future research works for better understanding and managing the KLS in Ayurveda

Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer

Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment

Implementation of the urban parameterization scheme to the Delhi model with an improved urban morphology

The current study highlights the importance of a detailed representation of urban processes in a numerical weather prediction model and emphasizes the need for accurate urban morphology data for improving the near-surface weather prediction over Delhi, a tropical Indian city. The Met Office Reading Urban Surface Exchange Scheme (MORUSES), a two-tile urban energy budget parameterization scheme, is introduced in a high resolution (330 m) model of Delhi. A new empirical relationship is established for the MORUSES scheme from the local urban morphology of Delhi. The performance is evaluated using both the newly developed empirical relationships (MORUSES-IND) and the existing empirical relationships for the MORUSES scheme (MORUSES-LON) against the default one-tile configuration (BEST-1t) for clear and foggy events and validations are performed against ground observations. MORUSES-IND exhibits a significant improvement in the diurnal evolution of the wind speed in terms of amplitude and phase, compared to the other two configurations. The screen temperature (Tscreen) simulations using MORUSES-IND reduce the warm bias, especially during the evening and night hours. The root-mean-square error of Tscreen is reduced up to 29 % using MORUSES-IND for both synoptic conditions. The diurnal cycle of surface energy fluxes is reproduced well using MORUSES-IND. The net longwave fluxes are underestimated in the model and biases are more significant during the foggy events partly due to the misrepresentation of fog. An urban cool island (UCI) effect is observed in the early morning hours during the clear sky conditions but it is not evident on foggy days. Compared to BEST-1t, MORUSES-IND represents the impact of urbanization more realistically which is reflected in the reduction of urban heat island and UCI in both synoptic conditions. Future works would improve the coupling between the urban surface energy budget and anthropogenic aerosols by introducing the MORUSES-IND in a chemistry aerosol framework model

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1-KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVFproduced IL-6 is important for SVF-stimulated tumor cell invasion in vitro, and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth