Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway

Background Despite development of current targeted therapies for medullary thyroid cancer (MTC), long-term survival remains unchanged. Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs. We hypothesize that these withanolides uniquely inhibit RET phosphorylation and the mammalian target of rapamycin (mTOR) pathway in MTC cells as a mechanism of antiproliferation and apoptosis. Methods MTC cells were treated with novel withanolides and MTC-targeted drugs. In vitro studies assessed cell viability and proliferation (MTS; trypan blue assays), apoptosis (flow cytometry with Annexin V/PI staining; confirmed by Western blot analysis), long-term cytotoxic effects (clonogenic assay), and suppression of key regulatory proteins such as RET, Akt, and mTOR (by Western blot analysis). Results The novel withanolides potently reduced MTC cell viability (half maximal inhibitory concentration [IC50], 270–2,850 nmol/L; 250–1,380 nmol/L for vandetanib; 360–1,640 nmol/L for cabozantinib) with induction of apoptosis at <1,000 nmol/L of drug. Unique from other targeted therapies, withanolides suppressed RET and Akt phosphorylation and protein expression (in a concentration- and time-dependent manner) as well as mTOR activity and translational activity of 4E-BP1 and protein synthesis mediated by p70S6kinase activation at IC50 concentrations. Conclusion Novel withanolides from Physalis selectively and potently inhibit MTC cells in vitro. Unlike other MTC-targeted therapies, these compounds uniquely inhibit both RET kinase activity and the Akt/mTOR prosurvival pathway. Further translational studies are warranted to evaluate their clinical potential

Cytotoxic Withanolide Constituents of Physalis longifolia

Fourteen new withanolides, 1–14, named withalongolides A–N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15–22). The structures of compounds 1–14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC50 values in the range between 0.067 and 9.3 μM

Collective Bargaining and Public Education Expenditures: Do Teachers’ Unions Propose and Voters Dispose?

This dissertation examines how collective bargaining by teachers’ unions affects public school expenditures in the United States, under different collective bargaining laws. It offers a unified empirical framework to test for the relative influence of the budget-maximizing bureaucracy model and the median voter model in explaining variations in public education expenditures. Drawing on existing classifications, it creates a more comprehensive classification of the strength of collective bargaining laws in different states. Using a national sample of nearly 3,250 unified school districts for 2011, it finds that districts with greater teacher collective bargaining spend more on their overall public education expenditures per pupil than districts with either lower teachers’ union density or no collective bargaining agreements. Teachers’ union density and collective bargaining agreements act as complements. The presence of teacher collective bargaining agreements in school districts appears to be a stronger determinant of district expenditures than their state collective bargaining laws; this applies to states where teacher collective bargaining is not banned by law. Through a decomposition of the variances explained, this dissertation suggests that teacher collective bargaining may be more influential than local resident characteristics for determining local public education expenditures, even though both models have some significant impact

Dorsal Spinal Intradural Intramedullary Epidermoid Cyst: A Rare Case Report and Review of Literature

Epidermoid cysts are commonly seen intracranial lesions but their occurrence in the spine is rare. They account for <1% of all the benign tumors of the spine. These are benign epithelial-lined cysts filled with keratin. They are classified into two types: congenital or acquired. Congenital epidermoid cysts are more commonly associated with spinal dysraphic states such as syringomyelia, dermal sinus and spina bifida whereas the acquired cysts are associated with repeated lumbar punctures. Based on the location, they can be extradural, intradural, extramedullary, or intramedullary. Most of the epidermoids are intradural extramedullary. Intramedullary epidermoid cysts are very uncommon. We report a case of a 6-year-old female patient with dorsal epidermoid cyst with neurological deficits. Magnetic resonance imaging of the spine showed a well-defined lesion from D9 to D12 which was hypointense on T1W1 and heterogeneously hyperintense on T2W2. Surgery was performed to excise the lesion and to decompress the spinal cord. Histopathological examination of the excised lesion confirmed it as an epidermoid cyst

A Study of Traumatic Cord Contusions - Management and Outcomes

Background: There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Aims: To study the long-term outcomes of patients presenting with spinal cord contusions and to compare the neurological outcomes in patients who underwent surgery and those who were managed conservatively. Materials and methods: A prospective study was conducted on all patients admitted with features of cord contusions and central cord syndrome for 2 years. Information gathered included mechanism of injury, previous neurological status, length of hospital stay and functional status. Group 1 included patients younger than 50 years of age, Group 2 included from 50 to 70 years of age and Group 3 had patients who were above 70 years of age. Results: Out of the 147 patients only 26 patients had a single level involvement. Around 61.6% of study subjects with injury of spinal cord at &gt;2 levels were found to have good outcome. Almost 54.5% of study subjects had good outcome in which spinal cord injury was at 2 levels and 34.6% of study subjects had good outcome among whom spinal cord injury was at 1 level only. The difference was found to be significant statistically. Patients undergoing early surgical intervention have better outcomes. Conclusion: It is concluded that Surgery is a better mode of management for cervical cord contusions

Strategic Placement of Solar Power Plant and Interline Power Flow Controllers for Prevention of Blackouts

In these post COVID times, the world is going through a massive restructuring which India can use to its benefit by attracting foreign industrial investment. The major requirement is a reliable and ecofriendly electrical power source. Of late, renewable energy sources have increasingly become popular as alternative source of electricity. They can provide immense aid in improving the reliability of the power system, when placed properly. The alternative integrated energy sources along with FACTS devices can provide a promising future for reliable power systems. In this paper, an effective location for the solar power unit and Interline Power Flow Controller using Line Severity Index is proposed in order to avoid contingencies. An Indian 62 bus system and IEEE 57 bus system are considered for the study. The Firefly algorithm is used to tune the IPFC in the Integrated Energy Systems scenario, for a dual objective function. The effect of placement of the solar unit and the optimized IPFC is analyzed and studied in detail in this paper

Strategic Placement of Solar Power Plant and Interline Power Flow Controllers for Prevention of Blackouts

In these post COVID times, the world is going through a massive restructuring which India can use to its benefit by attracting foreign industrial investment. The major requirement is a reliable and ecofriendly electrical power source. Of late, renewable energy sources have increasingly become popular as alternative source of electricity. They can provide immense aid in improving the reliability of the power system, when placed properly. The alternative integrated energy sources along with FACTS devices can provide a promising future for reliable power systems. In this paper, an effective location for the solar power unit and Interline Power Flow Controller using Line Severity Index is proposed in order to avoid contingencies. An Indian 62 bus system and IEEE 57 bus system are considered for the study. The Firefly algorithm is used to tune the IPFC in the Integrated Energy Systems scenario, for a dual objective function. The effect of placement of the solar unit and the optimized IPFC is analyzed and studied in detail in this paper

Minor Withanolides of Physalis longifolia: Structure and Cytotoxicity

This is the publisher's version, also available electronically from https://www.jstage.jst.go.jp/article/cpb/60/10/60_c12-00305/_article.In our recent publication on bioactive guided isolation of compounds from Physalis longifolia (Solanaceae) novel anti-proliferative agents withalongolides A (4) and B (5), and their highly cytotoxic analogues, withalongolide A 4,19,27-triacetate (4a) and withalongolide B 4,19-diacetate (5a) were elucidated. In this study, the two lead compounds (4, 5) were re-isolated in gram quantities for the purpose of further analogue preparation and in vivo testing that would continue to probe structure–activity relationships. During this process, two additional withanolides, named withalongolides O (1) and P (2), were elucidated. Their structures were determined by spectroscopic techniques with 1 being subsequently confirmed by X-ray crystallographic analysis. Utilizing a MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] viability assay, withalongolide O (1) and its 4,7-diaceatate (1a), both containing the functionalities of Δ2-1-oxo- in A ring, a 5β,6β-epoxy in B ring, and a lactone ring in the nine-carbon side chain, exhibited potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal lung fibroblast (MRC-5) cells with IC50 values in the range between 0.15 and 2.95 µM. In addition, the previously reported α orientation of 7-acetate group in acnistins C and D should be revised to the β orientation on the basis of NMR data comparison