4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17β-N-aryl-carboxamides: an approach to combined androgen blockade [5α-reductase inhibition with androgen receptor binding in vitro]

4-Aza-5α-androstan-3-one 17β-(N-substituted carboxamides) are potent human type 2 5α-reductase (5aR) inhibitors with generally poor binding to the human androgen receptor (hAR). When the 17-amide N-substituent included an aromatic residue, potent dual inhibitors of both type 1 and 2 5aR are produced, but hAR binding remained poor. Tertiary-substituted-17-amides have reduced inhibition of both 5aR isozymes. The addition of an N⁴-methyl substitutent to the A-ring profoundly increased hAR affinity and the addition of unsaturation to the A-ring (Δ¹) modestly augmented hAR binding. The unsubstituted carbanilides in the Δ¹-N⁴-methyl series show some selectivity for type 1 5aR over the type 2 isozyme, whereas addition of aryl substituents, particularly at the 2-position, increased type 2 5aR binding to provide dual inhibitors with excellent hAR binding, e.g. N-(2-chlorophenyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide (9c). Compounds of this type exhibit low nanomolar IC₅₀s for both human 5aR isozymes as well as the human androgen receptor. Kinetic analysis confirms that the prototype 9c displays reversible, competitive inhibition of both human isozymes of 5aR with K_i values of less than 10 nM. Furthermore, this compound binds to the androgen receptor with an IC₅₀ equal to 8 nM. Compounds in this series are projected to be powerful antagonists of testosterone and dihydrotestosterone action in vivo, with potential utility in the treatment of prostatic carcinoma (PC).     

A review on melatonin action as therapeutic agent in cancer

Background

Melatonin is a hormone which is produced from pineal gland in human and is said to have various impacts in human body like controlling sleep wake cycle, regulating the immune and cardiovascular system and regulating the peripheral organ functioning to name a few. Researchers have reported that the melatonin levels correlates with cancer risks.

Objective

In this review article, focus has been given to the therapeutic applications and impact of melatonin hormone in human behavior and physiologic activities. Through this article we aim in compiling the scattered information regarding melatonin and its various aspects of importance in human system.

Methods

We made an analysis of existing hypothesis and studies published on melatonin and circadian rhythm, factors effecting Melatonin secretions in body, sleep disturbances and cancer risks and melatonin therapy in cancer patients.

Results

Melatonin’s role as an endogenous synchronizer, growing evidence suggests its anti-oxidative activity as well as its having a role in modulating immune responses. Fluctuating melatonin levels can be boosted by ingesting products containing melatonin. A large portion of the examinations detailed by the researchers clearly conclude that keeping up an impeccable sleep-wake cycle and having a healthy diet is extremely important to keep up the regular melatonin levels and in order to stay fit.

Conclusions

Melatonin is considered as a critical hormone that controls and regulates many functions in our body. Melatonin production is emphatically related to the night time duration. Its most absolute biological role is to convey information to the body about day length for a variety of physiologic functions. In addition to melatonin’s role as an endogenous synchronizer, growing evidence suggests its anti-oxidative activity as well as its having a role in modulating immune responses. At present, a growing interest is focused on the validity of the anti-tumor mechanisms of melatonin.

     

Allergic Fungal Sinusitis Caused by Exserohilum rostratum and Literature Review

Mycopathologia - A case of allergic fungal sinusitis (AFS) caused by Exserohilum rostratum, proven by culture and histopathology of the biopsy material, is described. The identity of the isolate...     

First report of a hymenopteran parasitoid complex on jackfruit shoot and fruit borer Diaphania caesalis (Lepidoptera: Crambidae) from India

ABSTRACT

A survey of the species composition and relative abundance of Diaphania caesalis Walker (Lepidoptera: Crambidae) in plantations of jackfruit (Artocarpus heterophyllus Lam.) in three southern states along India’s western coast recorded thirteen species of primary parasitoids and one species of a hyperparasitoid, namely Tetrastichus pantnagerensis Khan (Hymenoptera: Eulophidae). Apanteles stantoni Ashmead (Hymenoptera: Braconidae) was the most dominant parasitoid and found in 35% of the parasitised host larvae in Karnataka, 38.5% in Kerala, and 33.1% in Tamil Nadu whereas the overall level of parasitisation, involving all the different parasitoids recorded, was approximately 41%–45% and did not vary significantly with location.     

A review on the genus Metarhizium as an entomopathogenic microbial biocontrol agent with emphasis on its use and utility in Mexico

Metarhizium is a genus of entomopathogenic fungi that was initially classified into three species and varieties. More recently, DNA sequencing has improved the phylogenetic resolution of Metarhizium which now includes 30 species. The insect host ranges vary within the genus and some species such as M. robertsii have broad host ranges, while others such as M. acridum show a narrow host range and are restricted to the order Orthoptera. Metarhizium spp. are ubiquitous naturally occurring soil inhabiting fungi, and some are rhizosphere colonisers and their diversity has been attributed to various selective factors (habitat type, climatic conditions, specific associations with plants and insect hosts). Metarhizium have been used for the biological control of insect pests that affect economically important agricultural crops and have been tested under laboratory and field conditions for the control of insect vectors of human disease, showing the effectiveness of the fungus against the target pest. In Mexico, Metarhizium species have been used for the control of insect pests such as the spittlebug (Hemiptera: Cercopidae), and locusts (Orthoptera) that affect crops such as corn, bean and sugarcane. Biosafety studies, such as dermal and intragastric tests in mammalian models have also been carried out to ensure safety to humans and other animals. Metarhizium shows great promise as an alternative to chemical insecticides that has relatively low impact on human health and the environment. Key features of Metarhizium for biocontrol of insects are outlined with special reference to their utility in Mexico.     

Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(+/-)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents

Use of ionizing radiation is essential for the management of many human cancers, and therapeutic hyperthermia has been identified as a potent radiosensitizer. Radiation therapy combined with adjuvant hyperthermia represents a potential tool to provide outstanding local-regional control for refractory disease. (Z)-(±)-2-(N-Benzylindol-3-ylmethylene)quinuclidin-3-ol (2) and (Z)-(±)-2-(N-benzenesulfonylindol-3-ylmethylene)quinuclidin-3-ol (4) were initially identified as potent thermal sensitizers that could lower the threshold needed for thermal sensitivity to radiation treatment. To define the structural requirements of the molecule that are essential for thermal sensitization, we have synthesized and evaluated a series of (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one (9), and (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol (10) analogs that incorporate a variety of substituents in both the indole and N-benzyl moieties. These systematic structure–activity relationship (SAR) studies were designed to further the development and optimization of potential clinically useful thermal sensitizing agents. The most potent analog was compound 10 (R¹ = H, R² = 4-Cl), which potently inhibited (93% inhibition at 50 μM) the growth of HT-29 cells after a 41 °C/2 h exposure.     

A comparative study evaluating the dose volume parameters in 3D conformal radiation of left sided whole breast irradiation including regional lymphnodes — a need of resource constrained countries

BackgroundThe purpose of this study was to compare four 3D conformal radiation techniques in treatment of left breast cancer patients.Materials and methodsRadiation was planned for 20 patients to the left breast and regional lymph nodes using four techniques: partially wide tangents, photon-photon mix, photon-electron mix and 30/70 photon-electron mix. All plans were evaluated for internal mammary nodes (IMN) coverage, hotspot and normal tissue constraints.ResultThe 85% of planning target volume (PTV) coverage was lesser for upper IMN than the lower IMN (below the lower border of the clavicular head) for all four techniques. The lower IMN coverage was better for partially wide tangent (80.46%) and photon-photon mix (88.88%). The lowest value of hotspot was seen in the partially wide tangent technique (112.69% ± 1.92). Hotspot is unacceptably high in both photon-electron mix and 30/70 photon-electron mix (> 120%). Left lung mean dose for all techniques on a pair-wise comparison showed no statistical difference. Left lung V20 values for partially wide tangent was 37.56% ± 8.17 and for photon-photon mix it was 40.49% ± 3.36. The mean heart dose with partially wide tangent was 9.43 ± 3.15 Gy and with photon-photon mix it was 10.10 ± 2.70 Gy. The mean heart dose for photon-electron mix was 7.56 ± 1.95 Gy and for 30/70 photon-electron mix it was 7.98 ± 2.16 Gy.ConclusionNo single technique satisfies all the criteria. The decision should be made on a case-by-case basis, considering the anatomy of the patient, availability of electron facilities and setup accuracy and reproducibility.     

A Granger causality measure for point process models of ensemble neural spiking activity

The ability to identify directional interactions that occur among multiple neurons in the brain is crucial to an understanding of how groups of neurons cooperate in order to generate specific brain functions. However, an optimal method of assessing these interactions has not been established. Granger causality has proven to be an effective method for the analysis of the directional interactions between multiple sets of continuous-valued data, but cannot be applied to neural spike train recordings due to their discrete nature. This paper proposes a point process framework that enables Granger causality to be applied to point process data such as neural spike trains. The proposed framework uses the point process likelihood function to relate a neuron's spiking probability to possible covariates, such as its own spiking history and the concurrent activity of simultaneously recorded neurons. Granger causality is assessed based on the relative reduction of the point process likelihood of one neuron obtained excluding one of its covariates compared to the likelihood obtained using all of its covariates. The method was tested on simulated data, and then applied to neural activity recorded from the primary motor cortex (MI) of a Felis catus subject. The interactions present in the simulated data were predicted with a high degree of accuracy, and when applied to the real neural data, the proposed method identified causal relationships between many of the recorded neurons. This paper proposes a novel method that successfully applies Granger causality to point process data, and has the potential to provide unique physiological insights when applied to neural spike trains.