The drugs controller general of India (DCGI) has granted permission to Cipla Limited, an Indian pharmaceutical company, to conduct Phase-I clinical trial of levormeloxifene for development as oral contraceptive for women as joint collaboration with CSIR-Central Drug Research Institute, Lucknow, India (CSIR-CDRI). Levormeloxifene is laevorotatory enantiomer of ormeloxifene, a benzopyran Selective Estrogen Receptor Modulator (SERM). Ormeloxifene is racemic mixture in equal quantities of levo- and dextro-enantiomers (compounds having same chemical composition but mirror-image 3-dimensional structures). In rats, levormeloxifene [Minimum Effective Dose (MED): 0.15 mg/kg/day] prevented pregnancy at almost half the dose than ormeloxifene (MED: 0.25 mg/kg/day) when administered orally covering the entire pre-implantation period. Levormeloxifene is equally effective as single 1 mg/kg dose when administered within 24 hours of coitus. In accordance with its higher relative binding affinity (RBA: 15.7±3.1 percent of estradiol-17β), levormeloxifene exhibited more potent estrogenic and antiestrogenic activities than the d-ormeloxifene (RBA: 2.10±0.9) or dl-ormeloxifene (RBA: 5.24±1.45). Besides, it shows promise in prevention of increased bone turnover and destructive joint diseases, and beneficial effect on serum lipids. This is the first comprehensive review providing relevant published information on structure, pharmaceutical properties, preparation, safety, pharmacokinetics and pharmacodynamics of levormeloxifene.

<p>Supplementary Figure S4. Schematic representation of the treatment regime of xenograft mice.</p>

<p>Supplementary Figure S1. ORM inhibits proliferation and invasion of PDAC cells.</p>

Aberrant regulation of β-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with β-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (−7.6 kcal/mol) to the active site of β-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial–mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of β-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising β-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.

Legends for Supplementary Figures S1-S4.

Supplementary Figure S3. ORM targets Sonic hedgehog signaling and inhibits NFĸB and Gli-1 transcriptional activity in PDAC cells.

Effect of ORM on cell cycle analysis and β-catenin localization. A. Histogram (i) and table (ii) represent the cell cycle distribution in DU145 cells. B. Confocal images of β-catenin, DAPI and merged images of control (i) and ORM treated (ii) PC3 cells.

Supplementary Figure S2. Effect of GDC-0449 and ORM on proliferation, clonogenicity and invasion of PDAC cells.

Effect of ORM on colonigenic and invasive potential of C4-2 cells: A. Effect of ORM on proliferation of C4-2 cells as determined by colony formation assay. B. Effect of ORM anchorage-independent growth of C4-2 cells as determined by soft agar colony Formation. Representative images showing colony formation in control and ORM treated groups. Bar graph indicates number of colony formed in control and ORM treated groups. Values represent mean {plus minus}SE of 3 plates. C. Effect of ORM on invasion of C4-2 cells as determined by Boyden chamber assay. i) Representative images showing invaded cells in control and ORM treated groups after 24 hrs. ii) Bar graph indicating average number of invaded cells in control and ORM treated groups.

<p>Supplementary Figure S1. ORM inhibits proliferation and invasion of PDAC cells.</p>

Effect of ORM on cell cycle analysis and β-catenin localization. A. Histogram (i) and table (ii) represent the cell cycle distribution in DU145 cells. B. Confocal images of β-catenin, DAPI and merged images of control (i) and ORM treated (ii) PC3 cells.

While destruction associated with floods during the monsoon season and cyclones receives wide attention, the extreme weather in the form of hail, lightning and high winds have also caused widespread devastation over India on a small spatial scale in recent years, especially during the period of March to June. India Meteorological Department (IMD) organized a special forecast improvement campaign during the period March to June of 2017–2019 when the weather forecasts at all offices of IMD were targeted towards an accurate forecast of the extreme form of thunderstorms and their associated impact in short range to nowcasting timescale and their dissemination. The purpose of this study is to quantify the improvement in operational thunderstorm forecast accuracy, in short range (24 h Severe Weather Guidance at subdivisional level) and nowcast scale (nowcasts for individual stations valid for 3 h and issued every three hours) during March to June of 2017 to 2019 and compare the same with the accuracy of previous years. As a result of these efforts, there has been a significant jump in forecast accuracy in the 24-h thunderstorm forecast as well as 3-h nowcast guidance for thunderstorms across the country. Probability of Detection (POD) scores for India as a whole for the 24-h thunderstorm forecast has doubled, while the false alarms (FAR) have remained at the same level as before the start of the forecast campaign. The results indicate that since a thunderstorm is a disastrous weather event, the forecasters generally tend towards spatial over-forecasting. However, this is not uniform across the months. There is systematic lower accuracy in the season transition months of March (winter to summer) and June (dry summer to wet summer). While POD decreases in both March and June, FAR decrease throughout the season. The significant evolution of atmospheric parameters (moisture in particular) as the season changes, favours the maturation of thunderstorms to cumulonimbus stage as the season progresses, and the problem of over forecasting in March becomes a problem of under forecasting of thunderstorms in June. Another reason for false alarms is the unconscious linkage of the thunderstorm with the pattern of rainfall occurrence. However, since all rain-giving clouds over India do not necessarily mature to the cumulonimbus stage, and vice versa, the two are not always related. This is particularly true for the more arid regions of the country, especially in March, where false alarms are higher. The poor density of reporting observatories compared to the mesoscale nature of the events may also increase false alarms, especially over the small maritime islands and the arid regions of the mainland. The accuracy of the All India 3 hourly station level nowcast also improved systematically since 2017. Despite these constraints, the improvements at all scales were possible due to (a) augmentation of observation network by the rapid expansion of Doppler radars network throughout the Indian mainland as well as the installation of a ground-based lightning detection network, (b) numerical modeling products introduced in 2019 to provide short-range forecasts for all aspects of convection; both of which are incorporated into the forecast framework through Standard Operating Procedures (SOP) to standardize the forecast procedure throughout the Indian region. A more objective forecast strategy, using data generated from a denser network of DWRs and crowdsourcing methods as well as more accurate mesoscale models will go a long way to further improve the thunderstorm forecasts.

Reactions on proton-rich nuclides drive the nucleosynthesis in core collapse supernovae (CCSNe) and in x-ray bursts (XRBs). CCSNe eject the nucleosynthesis products to the interstellar medium and hence are a potential inventory of p nuclei, whereas in XRBs nucleosynthesis powers the light curves. In both astrophysical sites the Ni-Cu cycle, which features a competition between Cu-59(p, alpha) Ni-56 and Cu-59(p, gamma) Zn-60, could potentially halt the production of heavier elements. Here, we report the first direct measurement of Cu-59(p, alpha) Ni-56 using a reaccelerated Cu-59 beam and a cryogenic solid hydrogen target. Our results show that the reaction proceeds predominantly to the ground state of Ni-56, and the experimental rate has been found to be lower than Hauser Feshbach based statistical model predictions. New results hints that the vp process could operate at higher temperatures than previously inferred and therefore remains a viable site for synthesizing the heavier elements.

Reactions on the proton-rich nuclides drive the nucleosynthesis in Core-Collapse Supernovae (CCSNe) and in X-ray bursts (XRBs). CCSNe eject the nucleosynthesis products to the interstellar medium and hence are a potential inventory of p-nuclei, whereas in XRBs nucleosynthesis powers the light curves. In both astrophysical sites the Ni-Cu cycle, which features a competition between $^{59}$Cu(p,$\alpha$)$^{56}$Ni and $^{59}$Cu(p,$\gamma$)$^{60}$Zn, could potentially halt the production of heavier elements. Here, we report the first direct measurement of $^{59}$Cu(p,$\alpha$)$^{56}$Ni using a re-accelerated $^{59}$Cu beam and cryogenic solid hydrogen target. Our results show that the reaction proceeds predominantly to the ground state of $^{56}$Ni and the experimental rate has been found to be lower than Hauser-Feshbach-based statistical predictions. New results hint that the $\nu p$-process could operate at higher temperatures than previously inferred and therefore remains a viable site for synthesizing the heavier elements.

In this paper, we show that the power function of sub E-function f n (x) is sub E-function.Furthermore, we establish some new integral inequalities of Hadamard type involving sub E-functions and concave E-functions.

The Proposed queuing model comprises of M serial service channels connected to N non-serial service channels. Inside every serial as well as non-serial service channel multiple parallel servers are allocated. Customers are allowed to balk as well as renege at any server inside the queuing model. Along with welsh because of long queue, reneging due to some urgent phone call or text information received, while waiting in the queue is applied in this queuing model. Using (Kelly, F.P., 1975. Networks of queues with customers of different types. Journal of Applied Probability, 12(3), pp.542–554) the difference-differential equations of the proposed model are obtained. Considering the system to be time independent, the time independent equations and corresponding solutions for various cases in the proposed queuing model are obtained. Further, it is submitted that the appearance process is Poisson, the administration time circulation is exponential, waiting space is finite, arrival of the customer depends upon the queue size at every service channel (serial/nonserial) and Service is done in random order rather than First come first serve principle.