Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.

Defining the role of mTOR pathway in the regulation of stem cells of glioblastoma.

The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, functions by forming two multiprotein complexes termed mTORC1 and mTORC2. Glioblastoma (GBM) is a uniformly fatal brain tumor that remains incurable partly due to the existence of untreatable cancer stem cells (CSC). The pathogenesis of GBM is largely due to the loss of the tumor suppressor gene PTEN, which is implicated in the aberrant activation of the mTOR pathway. The major cause of tumor recurrence, growth, and invasion is the presence of the unique population of CSC. Resistance to conventional therapies appears to be caused by both extensive genetic abnormalities and dysregulation of the transcription landscape. Consequently, CSCs have emerged as targets of interest in new treatment paradigms. Evidence suggests that inhibition of the mTOR pathway can also be applied to target CSCs. Here we explored the role of the mTOR pathway in the regulation of stem cells of GBM by treating them with inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126. A significant number of GBM tumors expressed stem cell marker nestin and activated mTOR (pmTORSer2448), with most tumor cells co-expressing both markers. The expression of stem cell marker NANOG was suppressed following rapamycin treatment. The neurospheres were disrupted following rapamycin and LY294002 treatments. Rapamycin or PP242 along with differentiating agent All-trans-retinoic acid reduced stem cell proliferation. Treatment with novel small molecule inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective. Torin1 and XL388 delay the process of self-renewal as compared to controls, whereas Torin2 halted self-renewal. Torin2 was able to eradicate tumor cells. In conclusion, Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM.

Increase of resistant starch content by hydrolysis of potato amylopectin and its microstructural studies by 2D and 3D imaging.

The effect of amylopullulanase treatment on recrystallization behaviour and the formation of resistant starch crystals have been investigated. Extracted potato starch (Solanum tuberosum) has been subjected to the enzymatic assisted bioprocessing without any physical or chemical treatment, where 120 min of incubation, 7 % (v/v) of enzyme and 8 mL/g of water content were found to be optimum to increase the resistant starch content by 41.88 %. The resistant starch crystals showed the characteristic behaviour of B-type allomorph with an increase in 21.32 % crystallinity. The modified crystals portrayed less reduction in actual weight when assessed by thermo-gravimetric analysis. The compact linear arrangement of the linear amylose chains within the crystallized granule of starch has been evidenced by Bright Field Microscopy. The microstructure of the resistant starch crystals showed 33.18 % reduction in porosity when the 3-dimensional structural form was analysed by X-ray micro-Computed Tomography.

Acute Urinary Retention due to Primary Pelvic Hydatid Cyst: A Rare Case Report and Literature Review.

Causes of urinary retention in old men include benign prostatic hyperplasia, prostatitis, prostate cancer, Scarring of the urethra or bladder neck as a result of injury or surgery, use of certain medicines particularly NSAIDs and opioid analgesics, constipation and neurogenic bladder. When the above common causes are not quite obvious by clinical examination and relevant investigations, then it is necessary to think of other rare diseases. It is with the above in our mind that a case of bladder outflow obstruction due to a large primary retrovesical hydatid cyst is herein reported in a 58-year-old man. Ultrasonography (USG) and Contrast Enhanced Computed Tomography (CECT) scan of the abdomen and pelvis of the patient revealed a large, multilocular, nonenhancing, cystic lesion in the rectovesical pouch having typical cartwheel appearance without any other intraabdominal organ involvement. These typical radiological characteristics led us to suspect the presence of a hydatid cyst. He underwent exploratory laparotomy where cystopericycstectomy was done. Pre-operative and post-operative albendazole prophylaxis was also given. In conclusion, hydatid cyst should always be considered in the differential diagnosis of pelvic cystic masses, specially in endemic regions.