Competition between anisometric and aliphatic entities: an unusual phase sequence with the induction of a phase in an n-alkane-liquid crystal binary system.

In this work, we demonstrate two important features that arise out of introducing a liquid-crystalline (LC) compound into the rotator phase matrix and the consequent competition between the anisometric segments of the LC moieties and the aliphatic units. First, we show that the change in the structural character of the mixed medium depends on which of the entities forms the minority concentration: in the case of this being the alkane, the two components of the binary system are nanophase segregated, whereas if the LC molecules are present in a small concentration, then the layered structure merely gets roughened without any segregation. The second and more significant result of the calorimetric and X-ray experiments, at low LC concentrations, is the induction of a rotator phase that leads to unusual phase sequence not reported hitherto. Possible scenarios for the molecular arrangement are discussed. A Landau model is also presented that explains some of the observed features.

A Novel RP-HPLC Method for Simultaneous Estimation of Vilanterol Trifenatate, Umeclidinium Bromide and Fluticasone Furoate in Inhalation Dry Powder Formulation.

The dry powder inhalation formulation containing vilanterol trifenatate, umeclidinium bromide and fluticasone furoate intended for the therapy of bronchospasm related to chronic obstructive pulmonary disease and bronchial asthma was selected for the development and validation of a novel, selective, accurate, precise, quick and cost-efficient reversed-phase, high-performance liquid chromatography method. Neither an official monograph nor a single method has yet been published for the simultaneous estimation of these three compounds, which makes this method novel. The stationary phase of an ACE-C18-PFP column (250 mm × 4.6 mm, 5 µ) was used with a mobile phase of 25-mM sodium perchlorate buffer (pH 2.5 adjusted with ortho-phosphoric acid) and acetonitrile (40:60% v/v) at a flow rate of 1 mL/min to optimize chromatographic variables. The column temperature was kept at 40°C, and detection was at 224 nm, which was the isosbestic point of these three drugs. Well-resolved good peak symmetry was obtained for all three molecules by isocratic elution in less than 10 min, and the retention times of vilanterol trifenatate, umeclidinium bromide and fluticasone furoate were found to be 3.7, 5.4 and 8.3 min, respectively. The proposed method was validated as per ICH Q2 (R1) guidelines, and the calibration curves were linear in concentration ranges of 5-35 µg/mL for vilanterol trifenatate, 5-80 µg/mL for umeclidinium bromide and 5-150 µg/mL for fluticasone furoate, with mean % recoveries of 99-100%. The limits of detection and quantitation are 0.15 and 0.45 µg/mL for vilanterol trifenatate, 0.58 and 1.77 µg/mL for umeclidinium bromide and 0.32 and 0.96 µg/mL for fluticasone furoate, respectively. Hence, the proposed RP-HPLC technique was successfully used to quantify the inhalation formulation containing all three compounds.

Diltiazem enhances the apoptotic effects of proteasome inhibitors to induce prostate cancer cell death.

Diltiazem is a calcium channel blocker used to treat cardiovascular ailments. In addition, reports suggest that diltiazem induces cell death, which could make it a drug of choice for the treatment of cancer associated with hypertension. The goal of this research was to determine whether diltiazem is capable of inducing apoptosis in prostate cancer cells, either alone or in combination with the proteasome inhibitors, lactacystin and bortezomib (Velcade). Bortezomib is approved for the treatment of multiple myeloma; unfortunately, it has side effects that limit its utility. Presumably these side effects could be decreased by reducing its dose in combination with another drug. We have previously shown that lactacystin induces apoptosis in LNCaP cells; here, we show that this effect was enhanced by diltiazem. Furthermore, in proteasome inhibitor-resistant DU145 cells, diltiazem alone did not induce apoptosis but decreased cytosolic calcium levels and induced mitochondrial fission; likewise, lactacystin did not induce apoptosis but up-regulated the proapoptotic protein Bik. However, increasing concentrations of diltiazem in combination with lactacystin or bortezomib induced apoptosis in a dose-dependent and synergistic manner. The combination of diltiazem and lactacystin also up-regulated the levels of Bik and released Bak from Bcl-xL, indicating the involvement of the Bcl2 family pathway in this apoptosis. In addition, the drug combination up-regulated GRP78, suggesting also the involvement of endoplasmic reticulum stress in the apoptotic response. Thus, our results demonstrate a potential therapeutic advantage of combining a frequently used calcium channel blocker with proteasome inhibitors in the treatment of prostate cancer.

Mobile Phones: Vital Addiction or Lethal Addiction? Mobile Phone Usage Patterns and Assessment of Mobile Addiction among Undergraduate Medical Students in Telangana, India.

BACKGROUND: Increased mobile phone usage among undergraduate medical students causes a detrimental effect on their health. The main focus of this study is to determine the pattern of mobile phone usage among undergraduate medical students in Hyderabad, India, and the detrimental effect on their health due to excess mobile use. MATERIALS AND METHODS: A cross-sectional study was conducted among undergraduate medical students from various medical colleges in Hyderabad, India, from September 2020 to January 2021. Data were collected from 626 respondents using a semistructured, pretested questionnaire. Smartphone Addiction Scale-Short Version (SAS-SV) was used to assess the risk of smartphone addiction. Microsoft Excel and SAS were employed to analyze the data. Associations were examined using Fisher's exact test. RESULTS: 100% of the respondents were using mobiles, with 83.2% spending more than 4 hours on them. Only 22% reported that no mobile use during classes. Half (51.6%) admitted to keeping their mobiles close by while sleeping. 84.3% used social networking apps via their mobiles. Common symptoms arising from prolonged mobile usage included eye strain (67.9%), blurred vision (31.4%), and numbness or tingling in palms (30.9%). 52.70% of the respondents were at high risk of mobile addiction according to SAS-SV. Screen time more than 4 hours was associated with high risk of mobile addiction (p < 0.0001). Significant association was found between high risk of mobile addiction and eye strain (p < 0.0001), blurry vision (p=0.0115), numbness/tingling in palms (p < 0.0001), and heat/tingling in the auditory area (p < 0.0001). CONCLUSION: The study shows the alarming rate of risk of smartphone addiction among medical students. Students can be encouraged to assess their mobile addiction status and become aware of the issue. More research may be performed to develop standardized tools for early identification of mobile addiction and appropriate therapies for its rectification.

Adaptations and Safety Modifications to Perform Safe Minimal Access Surgery (MIS: Laparoscopy and Robotic) During the COVID-19 Pandemic: Practice Modifications Expert Panel Consensus Guidelines from Academia of Minimal Access Surgical Oncology (AMASO).

The pandemic of COVID-19 across the globe triggered national lockdowns hampering normal working for all the essential services including healthcare. In order to reduce transmission and safety of patients and healthcare workers, the elective surgeries have been differed. The visits to the hospitals for follow-ups and consultations received temporary halt. However, we cannot halt the treatment for cancer patients who may or may not be COVID-19 positives. These are emergencies and should be treated ASAP. Conducting emergency surgeries during pandemic like COVID-19 is challenge for surgeons and the entire hospital infrastructure. The available information about COVID-19 and its propensity of contamination through droplets and aerosol need some modifications for conducting surgeries successfully without contaminating the hospital buildings, protecting healthcare teams and the patient. With these objectives, some modifications in the operating theater including surgical techniques for minimal access, laparoscopy, and robotic surgery are proposed in this review article. This review article also discusses the safety measures to be followed for the suspected or confirmed COVID-19 patient and the guidelines and recommendations for healthcare teams while treating these patients. Although there is little evidence of viral transmission through laparoscopic or open approaches, modifications to surgical practice such as the use of safe smoke evacuation and minimizing energy device used to reduce the risk of exposure to aerosolized particles to healthcare team are proposed in this review article.

Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice.

Immunomodulatory effect of ethanolic extract (50%) of M. oleifera leaves (MOE) has been studied in normal and immunosuppressed mice models. Different doses of MOE i.e. 125, 250 and 500 mg/kg body weight of mice were administered orally for 15 days. Cyclophosphamide at a dose of 30 mg/kg body weight was administered orally for the next 3 days. On day 16 and 19, hematological parameters like white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin level (Hb), percent neutrophils and organ weight were recorded. Effect of MOE on phagocytic activity of mice macrophages was determined by carbon clearance test. MOE showed significant dose dependent increase in WBC, percent neutrophils, weight of thymus and spleen along with phagocytic index in normal and immunosuppressed mice. The results indicate that MOE significantly reduced cyclophosphamide induced immunosuppression by stimulating both cellular and humoral immunity.

Correlation of Primary Tumour Size and Central Compartment Lymph Nodes Metastasis in Well Differentiated Thyroid Malignancies in a Tertiary Care Centre.

Central compartment lymph nodes are the first to be involved in thyroid carcinoma and associated with higher chances of recurrence. (1) Recurrence and revision surgery can be associated with a high risk of vocal cord paralysis and hypocalcemia. (2) However, the need for central compartment lymph nodes dissection routinely in all cases of thyroid malignancies is controversial considering the risk to recurrent laryngeal nerve and parathyroids. (3) The aim of the study was to evaluate the incidence of central compartment lymph nodes metastasis in well differentiated thyroid malignancy and their correlation with size of the primary tumour along with incidence of postoperative hypocalcemia and recurrent laryngeal nerve injury after central compartment lymph node dissection. Observational study 30 patients diagnosed as well-differentiated thyroid carcinoma after fine needle aspiration cytology and planned for total thyroidectomy and central compartment lymph node dissection in the Department of ENT at a tertiary care hospital in Mysuru were studied. After surgery, histopathological examination (HPE) of thyroid and lymph node specimen was done. Postoperatively, all patients were evaluated for hypocalcemia and recurrent laryngeal nerve injury. The incidence of central compartment lymph node metastasis after HPE was 66.6%. 80% cases with tumor size ≤ 1 cm and 64% cases having tumor size > 1 cm showed central compartment lymph node involvement. Overall Incidence of transient Hypocalcaemia was 40%. No case of recurrent laryngeal nerve palsy was observed. In well-differentiated thyroid malignancies we found a high incidence of central compartment lymph node involvement which was even higher with primary tumour of smaller size (≤ 1 cm). We did not find any incidence of permanent hypocalcemia and recurrent laryngeal nerve injury. So based on our study we emphasize on elective central compartment lymph node clearance to avoid recurrence.

Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents.

Inhibitors of histone deacetylases, including suberoylanilide hydroxamic acid (SAHA) and Trichostatin A, are a new class of anticancer agents. With potent chemotherapy effects in cancers, these agents are not obviously toxic in normal nonmalignant cells or tissues. However, their toxicity in kidney cells has not been carefully evaluated. Here, we demonstrate a potent apoptosis-inducing activity of SAHA in cultured renal proximal tubular cells. SAHA induces apoptosis at low micromolar concentrations. At 5 muM, SAHA induces 30 to approximately 40% apoptosis in 18 h. The apoptosis is accompanied by notable caspase activation; however, the general caspase inhibitor VAD can only partially suppress SAHA-induced apoptosis, suggesting the involvement of both caspase-dependent and -independent mechanisms. SAHA treatment leads to cytochrome c release from mitochondria, which is suppressed by Bcl-2 but not by VAD. Bcl-2 consistently blocks SAHA-induced apoptosis. During SAHA treatment, Bcl-2 and Bcl-XL decrease, and Bid is proteolytically cleaved, whereas Bax and Bak expression remains constant. Bid cleavage, but not Bcl-2/Bcl-XL decrease, is completely suppressed by VAD. SAHA does not activate p53, and pifithrin-alpha (a pharmacological p53 inhibitor) does not attenuate SAHA-induced apoptosis, negating a role of p53 in SAHA-induced apoptosis. SAHA induces histone acetylation, which is not affected by VAD, Bcl-2, or pifithrin-alpha. Trichostatin A can also induce apoptosis and histone acetylation in renal tubular cells. Together, the results have shown evidence for renal toxicity of histone deacetylase inhibitors. The toxicity may be related to protein acetylation and decrease of antiapoptotic proteins including Bcl-2 and Bcl-XL.

A dosimetric comparison between applicators used for brachytherapy in carcinoma cervix - A single-institute prospective study.

INTRODUCTION: Cervical cancer is the second most common cancer among Indian women. Radical radiotherapy with external beam radiation therapy (EBRT) and brachytherapy is the standard treatment for FIGO stage IB2 to IVA. An appropriate selection of brachytherapy applicator is needed according to the patient's anatomy. The two most commonly used applicators for intracavitary radiotherapy (ICR), Fletcher's and Henschke, have dosimetric differences which are not well studied with two-dimensional (2D)-based planning which is the most common method used for women with carcinoma cervix in India. The purpose of our study was to compare and evaluate the dosimetric differences between these two applicators, which would help in better selection of the applicator in cervical cancer patients. MATERIALS AND METHODS: This is a single-institute prospective study. Fifty patients randomly included in the study received EBRT and ICR by Ir192 HDR remote afterloading technique with computer-based 2D planning. Fletcher's and Henschke applicators were used alternately for first two fractions. RESULTS: The results of the study showed lower bladder and rectal doses with Fletcher's applicator and similar doses to point A for both applicators. However, point B doses are lower with Fletcher's applicator. CONCLUSION: Our results showed a favorable dosimetry with Fletcher's applicator in ICR of carcinoma cervix. The feasibility of placement is much better for Henschke but dosimetric advantages of Fletcher's encourage use of Fletcher's applicator for patients with favorable anatomy to reduce organs at risk doses but with the disadvantage of lower dose to point B.

Sensitization of TRAIL-resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin.

Due to its specificity and effectiveness, tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is being tested for cancer therapy. Inhibition of the function of heat shock protein 90 (HSP90) is under clinical trials for cancer therapy. However, some cancer cells are resistant to TRAIL, and at the dose required for inducing apoptosis, geldanamycin, a drug that inhibits HSP90 function, has shown adverse effects. Therefore, our working plan was to identify a sublethal dose of geldanamycin and combine it with TRAIL to induce apoptosis in TRAIL-resistant prostate cancer cells. Treatment of LNCaP with 250 nmol/L geldanamycin inhibited HSP90 function but did not induce significant apoptosis. However, combination of geldanamycin and TRAIL induced highly significant apoptosis in TRAIL-resistant LNCaP cells. In addition to inducing caspase activity and apoptosis, treatment with geldanamycin and TRAIL decreased inhibitor of kappaB (IkappaB) kinase (IKK) complex proteins, IKKalpha, IKKbeta, and IKKgamma. The loss of IKK affected IkappaBalpha/nuclear factor-kappaB (NF-kappaB) interaction and reduced nuclear transport of NF-kappaB, resulting in reduced NF-kappaB activity. Our data show increase in apoptosis using low, suboptimal dose of geldanamycin when used with TRAIL. These results provide a means to alleviate two problems: resistance to TRAIL and adverse effects of high-dose geldanamycin.

Therapeutic advantage of combining calcium channel blockers and TRAIL in prostate cancer.

Disruption of intracellular calcium initiates multiple cell-damaging processes, such as apoptosis. In normal cells, the levels of Ca(2+) are low in the mitochondria, whereas in apoptotic cells, Ca(2+) increases. Mitochondria uptake Ca(2+) via an inner membrane channel called the uniporter and extrude it into the cytoplasm through a Na(+)/Ca(2+) exchanger. Overload of Ca(2+) in the mitochondria in CGP-treated cells leads to its damage, thus affecting cellular function and survival. The goal of these experiments was to determine the importance of mitochondrial calcium ([Ca(2+)](m)) in apoptosis of prostate cancer cells. Furthermore, we have examined the advantages of increasing the [Ca(2+)](m) and treating the cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent apoptotic agent. Our results show that, under these treatment conditions, inhibiting the Na(+)/Ca(2+) exchanger using benzothiazepin CGP-37157 (CGP) did not induce apoptosis. However, combination of CGP and TRAIL increased the apoptotic response approximately 25-fold compared with control. Increase in apoptosis followed enhanced levels of [Ca(2+)](m) and was accompanied by pronounced mitochondrial changes characteristic of mitochondria-mediated apoptosis. Experiments with calcium ionophores showed that mere increase in cytosolic and/or mitochondrial Ca(2+) was not sufficient to induce apoptosis. These results have therapeutic implications as inhibitors of Na(+)/Ca(2+) exchanger are being used for treating some neurologic and cardiologic ailments, and TRAIL induces apoptosis preferentially in cancer cells. Furthermore, this system provides an excellent model to investigate the role of [Ca(2+)](m) in apoptosis.

Mitochondria from TRAIL-resistant prostate cancer cells are capable of responding to apoptotic stimuli.

TNFalpha-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in prostate cancer cells. However, some prostate cancer cells, such as LNCaP are resistant to TRAIL. In addition to the involvement of several pathways in the TRAIL-resistance of LNCaP, it has been shown that mitochondrial response to TRIAL is low in these cells. Therefore, in this study, using in vitro cell free and reconstitution models, we have demonstrated that mitochondria from these cells are capable of responding to apoptotic stimuli. Furthermore, experiments to determine the influence of cytochrome c on apoptotic response noted that incubation of cytosol with exogenous cytochrome c induced truncation of Bid. We have demonstrated that truncation of Bid by exogenous cytochrome c is mediated through the activation of caspases-9 and -3. Incubation of cytosol with recombinant caspases-9 and -3 in the absence or presence of inhibitors showed that activation of caspase-9, leading to the activation of caspase-3 was necessary for the truncation of Bid. Published results indicate that in apoptotic cells cytochrome c is released from the mitochondria in two installments, an early small amount and a late larger amount. Our results suggest that the initial release of cytochrome generates tBid that is capable of translocation into the mitochondria causing further release of cytochrome c. Thus, in addition to providing functional explanation for the biphasic release of cytochrome c from mitochondria, we demonstrate the presence of a feedback amplification of mitochondrial apoptotic signal.

Combination of proteasomal inhibitors lactacystin and MG132 induced synergistic apoptosis in prostate cancer cells.

The proteasome inhibitor Velcade (bortezomib/PS-341) has been shown to block the targeted proteolytic degradation of short-lived proteins that are involved in cell maintenance, growth, division, and death, advocating the use of proteasomal inhibitors as therapeutic agents. Although many studies focused on the use of one proteasomal inhibitor for therapy, we hypothesized that the combination of proteasome inhibitors Lactacystin (AG Scientific, Inc., San Diego CA) and MG132 (Biomol International, Plymouth Meeting, PA) may be more effective in inducing apoptosis. Additionally, this regimen would enable the use of sublethal doses of individual drugs, thus reducing adverse effects. Results indicate a significant increase in apoptosis when LNCaP prostate cancer cells were treated with increasing levels of Lactacystin, MG132, or a combination of sublethal doses of these two inhibitors. Furthermore, induction in apoptosis coincided with a significant loss of IKKalpha, IKKbeta, and IKKgamma proteins and NFkappaB activity. In addition to describing effective therapeutic agents, we provide a model system to facilitate the investigation of the mechanism of action of these drugs and their effects on the IKK-NFkappaB axis.

Mifepristone pretreatment overcomes resistance of prostate cancer cells to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL).

Examination of the effects of TRAIL (tumor necrosis factor alpha-related apoptosis-inducing ligand) showed higher apoptotic response in LNCaP C4-2, whereas LNCaP were resistant. However, treatment of LNCaP with Mifepristone, an antiprogestin, before TRAIL induced significant apoptosis, similar to the levels observed in LNCaP C4-2. Experiments to determine the reasons for altered response of the cell lines showed no significant differences in death/decoy receptors and caspase-8 activity. However, treatment induced increased truncation of Bid and activation of caspases -9, -7, and -3 in LNCaP C4-2. Time course experiments showed that caspase-8 was activated before the involvement of mitochondrial pathway, and caspase-9 was responsible for activation of caspases -7 and -3. Use of specific caspase inhibitors demonstrated the presence of a short-loop feedback activation of Bid. Published reports suggested that increased phosphorylation of Akt was responsible for resistance of LNCaP to TRAIL. However, no significant differences were noticed in the levels of phosphorylated Akt in TRAIL-resistant LNCaP and TRAIL-sensitive LNCaP C4-2. On the basis of our results, it is suggested that the differences in response of the two cell lines to TRAIL is at the mitochondrial level.

Role of genomics-based strategies in overcoming chemotherapeutic resistance.

As cancer is being recognized as a failure of apoptosis, apoptosis-based strategies are being designed. Caspases are critical for the induction of apoptosis and their decreased expression is correlated with increased grade of cancer, while increased expression of caspases rendered the cancer cells susceptible to chemotherapy. However, the endogenous functions of caspases are inhibited by inhibitors of apoptosis (IAPs) that bind activated caspases. Methods to suppress the function of IAP induced apoptosis in chemo-resistant cancer cells. The function of IAPs is inhibited by Second Mitochondria-Derived Activator Of Caspase (Smac) or Direct IAP Binding Protein With Low Pi (DIABLO). Upon apoptotic stimulus Smac/DIABLO is released from the mitochondria, which binds to IAPs and inhibits their caspase-binding activity. Overexpression of Smac/DIABLO sensitized neuroblastoma to TRAIL (TNFalpha-Related Apoptosis-Inducing Ligand). Activation of TRAIL pathway has become an important method of inducing apoptosis except in TRAIL-resistant cells. However, treatment of these cells with other cytotoxic drugs sensitizes them to TRAIL, providing effective therapeutic advantages. In addition to activating apoptotic pathways, inhibiting or suppression of cell proliferation is necessary to sensitize cancer cells to apoptosis. Critical among these proteins are NFkappaB and Akt. NFkappaB blocked apoptosis by interfering with the function of TNFalpha/TRAIL and/or through the activation of antiapoptotic proteins of the Bcl2 family. Similarly, Akt mediate cell survival via the regulation of cell survival proteins and by blocking the function of proapoptotic Bad by phosphorylation. Altering the expression of Akt by dominant negative constructs or by expression of PTEN interferes with Akt function. In summary, this review points out the complexity of interactions of the cell survival and death pathways and highlights some methods to manipulate them to achieve therapeutic advantage.

Mifepristone-induced secretion of transforming growth factor beta1-induced apoptosis in prostate cancer cells.

Successful therapy should induce apoptosis in prostate cancer cells irrespective of their androgen response. We have investigated the possibility of utilizing Mifepristone and Tamoxifen as treatment options for prostate cancer cells. Because preliminary results demonstrated induction of apoptosis by these drugs, the mechanism of induction of apoptosis was investigated. LNCaP-C4 prostate cancer cells were treated with Mifepristone and/or Tamoxifen. To confirm cytotoxic effects, nude mice with LNCaP-C4 xenografts were treated with Mifepristone and Tamoxifen. Cell viability was assayed using Sulforhodamine B (SRB) assay and DNA fragmentation was measured by ELISA. Culture media from vehicle- and drug-treated cells were collected and secretion of transforming growth factor beta1 (TGFbeta1) was estimated by ELISA. Role of TGFbeta1 was confirmed by inhibiting its function using TGFbeta1 antibody or M6P, which blocked activation of TGFbeta1. Apoptotic effects were determined by immunoblots of cytochrome c levels in cytosol and by in vitro colorimetric assay of caspase-3 activity. Results showed that although both drugs induced apoptosis in LNCaP-C4 cells, Mifepristone was more effective. The effects of these drugs on xenografts confirmed in vitro results. It was hypothesized that drug-induced secretion of TGFbeta1 may be responsible for induction of apoptosis. Neutralization of TGFbeta1 with an antibody or blocking the activation of TGFbeta1 by M6P abrogated the effects of Mifepristone and Tamoxifen confirming our hypothesis. Furthermore, treatment with Mifepristone and/or Tamoxifen released cytochrome c into the cytoplasm and induced activity of caspase-3, providing evidence that the drug-stimulated secretion of TGFbeta1 was responsible for induction of apoptosis in these cells. In conclusion, both Mifepristone and Tamoxifen induced apoptosis mediated through TGFbeta1. However, no critical advantage was noted by the addition of Tamoxifen to Mifepristone treatment.

Reduced response of prostate cancer cells to TRAIL is modulated by NFkappaB-mediated inhibition of caspases and Bid activation.

We describe the effects of tumor necrosis factor alpha-related apoptosis inducing ligand (TRAIL) on the induction of apoptosis in two related prostate cancer cell lines, PC3AR and PC3Neo. TRAIL is a potent drug, which induces apoptosis preferentially in cancer cells. Treatment of prostate cancer cells, reduced survival by approximately 41% in PC3AR, but only approximately 18% PC3Neo were killed. Western analysis demonstrated that increased apoptotic response of PC3AR cells may be due to differential response of death receptors DR4, DR5 and decoy receptors DcR1 and DcR2. Caspases-8, -9, -3 and Bid were highly activated in PC3AR cells compared to PC3Neo. Furthermore, lower apoptotic response of PC3Neo was probably due to higher expression of NFkappaB. Blocking the function of NFkappaB by adenoviral infection of mutated IkappaB, increased apoptotic response confirming the influence of NFkappaB. Thus, we have demonstrated the role of NFkappaB in the differential response of prostate cancer cells to TRAIL.

Laparoscopic Nissen fundoplication; results of a prospective pilot study.

Laparoscopic fundoplication is rapidly becoming the surgical procedure of choice in western countries for the management of gastro-oesophageal reflux disease (GERD). Experience with this technique is limited in India. Most operations continue to be performed through the traditional open technique, thus denying the advantage of a minimal invasive approach to patients. This study was done to evaluate the feasibility and short term results of laparoscopic Nissen fundoplication. Between June 2000 and March 2002, a total of 10 patients with GERD refractory to medical therapy or requiring daily treatment underwent laparoscopic Nissen fundoplication. Preoperative evaluation included scoring of symptoms, oesophagogastroduodenoscopy, barium swallow and nuclear scan. The intraoperative and post-operative course of the patients was recorded. At 3 months post-surgery, patients were re-evaluated using pre-operative symptom scores and investigations to assess the benefit of and complications associated with surgery. Laparoscopic nissen fundoplication was successfully completed in all the patients. Follow up ranged from 3 to 18 months with a mean of 5.9 months. The mean symptom score decreased from 10.1 pre-operatively to 1.7 (p value < 0.001). Eight out of 9 patients (88%) had endoscopic resolution of oesophagitis. Seven patients (70%) were off medication following surgery while the remaining 3 (30%) were taking medication intermittently. Overall, 80% of the patients were satisfied with the surgery. One patient required re-exploration due to bleeding from a short gastric vessel. The most frequent post-operative complication was temporary dysphagia in 60% of patients, which improved with conservative management over 2 to 3 weeks. We concluded that laparoscopic Nissen fundoplication is a safe and effective procedure to treat patients with GERD.

Mitofusin 1 degradation is induced by a disruptor of mitochondrial calcium homeostasis, CGP37157: a role in apoptosis in prostate cancer cells.

Mitochondria constantly divide (mitochondrial fission) and fuse (mitochondrial fusion) in a normal cell. Disturbances in the balance between these two physiological processes may lead to cell dysfunction or to cell death. Induction of cell death is the prime goal of prostate cancer chemotherapy. Our previous study demonstrated that androgens increase the expression of a mitochondrial protein involved in fission and facilitate an apoptotic response to CGP37157 (CGP), an inhibitor of mitochondrial calcium efflux, in prostate cancer cells. However, the regulation and role of mitochondrial fusion proteins in the death of these cells have not been examined. Therefore, our objective was to investigate the effect of CGP on a key mitochondrial fusion protein, mitofusin 1 (Mfn1), and the role of Mfn1 in prostate cancer cell apoptosis. We used various prostate cancer cell lines and western blot analysis, qRT-PCR, siRNA, M30 apoptosis assay and immunoprecipitation techniques to determine mechanisms regulating Mfn1. Treatment of prostate cancer cells with CGP resulted in selective degradation of Mfn1. Mfn1 ubiquitination was detected following immunoprecipitation of overexpressed Myc-tagged Mfn1 protein from CGP-treated cells, and treatment with the proteasomal inhibitor lactacystin, as well as siRNA-mediated knockdown of the E3 ubiquitin ligase March5, protected Mfn1 from CGP-induced degradation. These data indicate the involvement of the ubiquitin-proteasome pathway in CGP-induced degradation of Mfn1. We also demonstrated that downregulation of Mfn1 by siRNA enhanced the apoptotic response of LNCaP cells to CGP, suggesting a likely pro-survival role for Mfn1 in these cells. Our results suggest that manipulation of mitofusins may provide a novel therapeutic advantage in treating prostate cancer.

Polarity-sensitive transient patterned state in a twisted nematic liquid crystal driven by very low frequency fields.

We report, for a rodlike nematic liquid crystal with small positive dielectric and conductivity anisotropies, and in the 90°-twisted configuration, low frequency (<2 Hz) square wave electric field generated Carr-Helfrich director modulation appearing transiently over a few seconds at each polarity reversal and vanishing almost completely under steady field conditions. Significantly, the instability is polarity sensitive, with the maximum distortion localized in the vicinity of the negative electrode, rather than in the midplane of the layer. This is revealed by the wave vector alternating in the two halves of the driving cycle between the alignment directions at the two substrates. Besides the Carr-Helfrich mechanism, quadrupolar flexoelectric polarization arising under electric field gradient is strongly indicated as being involved in the development of the transient periodic order. Similar transient instability is also observed in other nematic compounds with varying combinations of dielectric and conductivity anisotropies, showing its general nature. The study also deals with various characteristics of the electro-optic effect that emerge from the temporal variation of optical response for different driving voltages, frequencies, and temperatures.