Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks.

Fibrosis has been characterized as a global health problem and ranks as one of the primary causes of organ dysfunction. Currently, there is no cure for pulmonary fibrosis, and limited therapeutic options are available due to an inadequate understanding of the disease pathogenesis. The absence of advanced in vitro models replicating dynamic temporal changes observed in the tissue with the progression of the disease is a significant impediment in the development of novel antifibrotic treatments, which has motivated research on tissue-mimetic three-dimensional (3D) models. In this review, we summarize emerging trends in preparing advanced lung models to recapitulate biochemical and biomechanical processes associated with lung fibrogenesis. We begin by describing the importance of in vivo studies and highlighting the often poor correlation between preclinical research and clinical outcomes and the limitations of conventional cell culture in accurately simulating the 3D tissue microenvironment. Rapid advancement in biomaterials, biofabrication, biomicrofluidics, and related bioengineering techniques are enabling the preparation of in vitro models to reproduce the epithelium structure and operate as reliable drug screening strategies for precise prediction. Improving and understanding these model systems is necessary to find the cross-talks between growing cells and the stage at which myofibroblasts differentiate. These advanced models allow us to utilize the knowledge and identify, characterize, and hand pick medicines beneficial to the human community. The challenges of the current approaches, along with the opportunities for further research with potential for translation in this field, are presented toward developing novel treatments for pulmonary fibrosis.

Novel study on enhancing the ignition pattern of waste and inedible feedstock in a modified diesel engine-enhancing its effectiveness as renewable alternative.

The objective of the present investigation is to enhance the performance of diesel engine using Capparis spinoza fatty acid distillate biodiesel (CFAB100) at various compression ratios. The experiments were carried out at compression ratios of 16.5:1, 17.5:1, 18.5:1, and 19.5:1. It was noted that an increase in compression ratio from 16.5 to 18.5 resulted in better engine characteristics for CFAB100 and reduced at compression ratio 19.5. Brake-specific fuel consumption of CFAB100 decreased from 0.42 to 0.33 kg/kWh with an increase in compression ratio. The brake thermal efficiency of CFAB100 at a compression ratio of 16.5 is 29.64% lower than diesel, whereas it is 11.32% low at a compression ratio of 18.5. The brake thermal efficiency of CFAB100 is 26.03% higher at a compression ratio of 18.5 compared to 16.5. Due to shorter ignition delay and reduced premixed combustion, the net heat release rate of CFAB100 is lower than diesel at all compression ratios. The peak cylinder pressure for diesel is 56.21 bar, and CFAB100 at compression ratios 16.5, 17.5, 18.5, and 19.5 were 52.36, 55.12, 61.02 and 58.25 bar at full load condition. CFAB100, at a compression ratio of 18.5, had the highest nitrogen oxide emissions (2400 ppm). Carbon monoxide, unburnt hydrocarbon, and smoke showed an average reduction of 46.58%, 40.68%, and 54.89%, respectively, when the compression ratio varied between 16.5 and 19.5. At an optimum compression ratio of 18.5, the CFAB100 resulted in improved performance and emission characteristics that can replace diesel to a possible extent.

A correlation study between mean platelet volume and platelet aggregation study in acute coronary syndrome patients.

INTRODUCTION: Platelets play an important role in cardiovascular disease mainly in the development of acute thrombotic events. Elevated platelet indices have been proposed as a risk factor for acute coronary syndrome (ACS). It remains uncertain whether increased platelet indices are the result or the cause of ACS. AIM AND OBJECTIVE: This study aimed to correlate mean platelet volume (MPV) and platelet aggregation response to know the functional status of platelets based on their size. MATERIALS AND METHODS: A total of 50 patients with ST-segment elevation ACS (STE-ACS) or non-ST-segment elevation ACS (NSTE-ACS) were included and their MPV was measured and platelet aggregometry was performed. Patients were divided into two groups, patients with MPV ≤9.1 fl as group 1 and those with MPV >9.1 fl as group 2. The mean maximum platelet aggregation response (MMPAR) with ADP, Collagen, and Epinephrine, of both the groups, were compared. MMPAR to ADP, Collagen, and Epinephrine in group 1 was 74.47%, 66.13%, and 72.9%, respectively, and in group 2, 72.94%, 59.97%, and 72.43%, respectively. There was no statistically significant difference in the MMPAR to ADP, Collagen, and Epinephrine among the two groups. CONCLUSION: Increased MPV does not indicate the platelets are hyperreactive. An increase in MPV may be because of the increased release of immature platelets from bone marrow as there is increased consumption of platelets at the site of thrombus formation in ACS.

Factors associated with mortality among moderate and severe patients with COVID-19 in India: a secondary analysis of a randomised controlled trial.

OBJECTIVE: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma. DESIGN: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease. SETTING: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020. PARTICIPANTS: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed. PRIMARY OUTCOME MEASURE: Factors associated with all-cause mortality at 28 days after enrolment. RESULTS: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death. CONCLUSION: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death. TRIAL REGISTRATION NUMBER: CTRI/2020/04/024775.

Myosin IIA and formin dependent mechanosensitivity of filopodia adhesion.

Filopodia, dynamic membrane protrusions driven by polymerization of an actin filament core, can adhere to the extracellular matrix and experience both external and cell-generated pulling forces. The role of such forces in filopodia adhesion is however insufficiently understood. Here, we study filopodia induced by overexpression of myosin X, typical for cancer cells. The lifetime of such filopodia positively correlates with the presence of myosin IIA filaments at the filopodia bases. Application of pulling forces to the filopodia tips through attached fibronectin-coated laser-trapped beads results in sustained growth of the filopodia. Pharmacological inhibition or knockdown of myosin IIA abolishes the filopodia adhesion to the beads. Formin inhibitor SMIFH2, which causes detachment of actin filaments from formin molecules, produces similar effect. Thus, centripetal force generated by myosin IIA filaments at the base of filopodium and transmitted to the tip through actin core in a formin-dependent fashion is required for filopodia adhesion.

Incidence of thrombosis in perioperative and non-operative myocardial infarction.

BACKGROUND: The contribution of thrombosis to the aetiology of perioperative myocardial infarction (MI) is uncertain. We used optical coherence tomography (OCT) to determine the presence of thrombus and plaque morphology in patients experiencing a perioperative MI and matched patients experiencing a non-operative MI using OCT. METHODS: We conducted a single-centre, prospective, cohort study. Thirty patients experiencing a perioperative MI and 30 matched patients experiencing a non-operative MI, without ST elevation, underwent OCT to determine the presence of thrombus and culprit lesion plaque morphology. Angiography and OCT were performed a mean of 1.93(1.09) days and 1.53(0.68) days after the onset of perioperative and non-operative MI, respectively. OCT images were evaluated by an independent core laboratory without knowledge of whether the patient had suffered a perioperative or non-operative MI. RESULTS: We identified thrombus at the culprit lesion in four of 30 patients (13.3%) who experienced a perioperative MI and in 20 of 30 patients (66.7%) who experienced a non-operative MI, P<0.01. The only non-culprit lesion with thrombus was in a perioperative MI patient who also had a culprit lesion thrombus. Perioperative and non-operative MI culprit lesions demonstrated fibroatheroma in 18 patients (60.0%) us 20 patients (66.7%), respectively (P=0.52) and thin cap fibroatheroma in one patient (3.3%) us five patients (16.7%), respectively (P=0.11). One perioperative MI patient (3.3%) suffered a cardiac death and no non-operative MI patient died during the 30-day follow-up. CONCLUSIONS: Thrombosis was less common in perioperative than non-operative MI, despite similar underlying plaque morphology.

A mononuclear iron carbonyl complex [Fe(µ-bdt)(CO)2(PTA)2] with bulky phosphine ligands: a model for the [FeFe] hydrogenase enzyme active site with an inverted redox potential.

A mononuclear hexa-coordinated iron carbonyl complex [Fe(µ-bdt)(CO)2(PTA)2] 1 (bdt = 1,2-benzenedithiolate; PTA = 1,3,5-triaza-7-phosphaadamantane) with two bulky phosphine ligands in the trans position was synthesized and characterized by X-ray structural analysis coulometry data, FTIR, electrochemistry and electronic structure calculations. The complex undergoes a facilitated two-electron reduction 1/12- and shows an inverted one-electron reduction for 1/1- at higher potentials. Electrochemical investigations of 1 are compared to the closely related [Fe(bdt)(CO)2(PMe3)2] compound. A mechanistic suggestion for the hydrogen evolution reaction upon proton reduction from acid media is derived. The stability of 1 in both weak and strong acids is monitored by cyclic voltammetry.

A survey of doctors at a UK teaching hospital to assess understanding of recent changes to consent law.

BACKGROUND: The UK Supreme Court recently ruled that when consenting patients for treatments or procedures, clinicians must also discuss any associated material risks. We surveyed medical staff at a large UK teaching hospital in order to ascertain knowledge of consent law and current understanding of this change. MATERIALS AND METHODS: Email survey sent to medical staff in all specialities at Norfolk and Norwich University Hospital in February 2016. RESULTS: 245 responses (141 Consultants and 104 junior doctors, response rate 32%). 82% consent patients for procedures at least monthly and 23% daily. 31% were not familiar with the concept of material risk. 35% were familiar with the recent change in consent law, 41% were not. 18% were "very uncertain" and 64% "a little uncertain" that their consenting process meets current legal requirements. >92% think that landmark cases and changes in law should be discussed through professional bodies and circulated better locally. CONCLUSION: The majority were not familiar with the concept of material risk and recent legal changes. A majority were not confident that their practice meets current requirements, suggesting that recent changes in consent law may not be widely understood at this hospital. We suggest more guidance and education may be necessary than is currently available. Increased understanding of recent changes to consent law will reduce the risk taken by NHS trusts and offer patients a service compliant with Supreme Court guidance.

Abdominal wall ectopic testis torsion mimicking a Spigelian hernia in an adult.

We report an unusual case of an ectopic testis identified in a 37-year-old man presenting with acute severe right iliac fossa pain and an irreducible mass. Initially diagnosed as a Spigelian hernia, computed tomography and ultrasonography identified the presence of an ectopic testis in the abdominal wall. Interparietal testicular ectopia is an extremely rare condition. We present and discuss the first case in the literature of an ectopic testis located between the internal and external oblique muscle layers of the anterior abdominal wall in an adult.

A Case of Hepatopulmonary Syndrome.

We report the case of a 52-year-old female, a known case of Chronic Liver Disease with portal hypertension. She presented with dyspnoea, platypnoea, melena, cyanosis, clubbing and orthodeoxia. She had oesophageal varices and splenomegaly indicating portal hypertension. Her arterial blood gas revealed hypoxaemia and orthodeoxia. From this clinical background and investigation, a diagnosis of hepatopulmonary syndrome was made. Patient was managed conservatively as she was not willing for liver transplantation.

Increase in upper tropospheric and lower stratospheric aerosol levels and its potential connection with Asian pollution.

Satellite observations have shown that the Asian Summer Monsoon strongly influences the upper troposphere and lower stratosphere (UTLS) aerosol morphology through its role in the formation of the Asian Tropopause Aerosol Layer (ATAL). Stratospheric Aerosol and Gas Experiment II solar occultation and Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) lidar observations show that summertime UTLS Aerosol Optical Depth (AOD) between 13 and 18 km over Asia has increased by three times since the late 1990s. Here we present the first in situ balloon measurements of aerosol backscatter in the UTLS from Western China, which confirm high aerosol levels observed by CALIPSO since 2006. Aircraft in situ measurements suggest that aerosols at lower altitudes of the ATAL are largely composed of carbonaceous and sulfate materials (carbon/sulfur elemental ratio ranging from 2 to 10). Back trajectory analysis from Cloud-Aerosol Lidar with Orthogonal Polarization observations indicates that deep convection over the Indian subcontinent supplies the ATAL through the transport of pollution into the UTLS. Time series of deep convection occurrence, carbon monoxide, aerosol, temperature, and relative humidity suggest that secondary aerosol formation and growth in a cold, moist convective environment could play an important role in the formation of ATAL. Finally, radiative calculations show that the ATAL layer has exerted a short-term regional forcing at the top of the atmosphere of -0.1 W/m2 in the past 18 years. KEY POINTS: Increase of summertime upper tropospheric aerosol levels over Asia since the 1990s Upper tropospheric enhancement also observed by in situ backscatter measurements Significant regional radiative forcing of -0.1 W/m2.

Giant Cell Lesions of Lungs: A Histopathological and Morphometric Study of Seven Autopsy Cases.

INTRODUCTION: Macrophages undergo fusion to form multinucleated giant cells (MGC) in several pathologic conditions. The exact mechanism of their generation is still unclear. MGC are a common feature of granulomas that develop during various inflammatory reactions. AIM: To study the histopathological features of giant cell lesions in lungs and correlate the characteristics of giant cells with other histopathological findings. Also, to determine the utility of morphometry to differentiate foreign body and Langhans MGC. MATERIALS AND METHODS: Seven cases were analysed. Specimen of lungs was grossed, sectioned and processed. Routinely, tissue sections were stained by Haematoxylin and Eosin (H&E) stain. Polarizing microscopy and special stains were employed in selected cases. Granulomas and MGC were counted and measured. Several other parameters like location, distribution, type and number of MGC, associated predominant inflammatory component and nature of granulomas were analysed. RESULTS: Five patterns of lesions were observed in seven cases. Aspiration pneumonia was seen in three cases (42.85%) and constituted the most common pattern. However, aspiration pneumonia as the only cause of MGC was seen in only one case (14.28%). Pulmonary tuberculosis and asteroid bodies constituted two cases (28.57%) each. Cryptococcal pneumonia and cholesterol clefts constituted one case (14.28%) each. Crypococci were demonstrated to be positively birefringent by polarized microscopy on Ziehl-Neelsen stained sections. Based on statistical analysis of morphometric data, a new index (NP index) was proposed to statistically categorize MGC into foreign body type and Langhans type. NP index value of ≤0.016 was found to be statistically significant (p<0.005) in foreign body MGC. It had high sensitivity and efficacy. CONCLUSION: MGC may not be always associated with granulomas. The mechanisms that lead to the occurrence of MGC, independent of granuloma needs to be elucidated. Morphometry may serve as a useful aid. But a pathologist has to rely on the morphological details to categorize MGC.

Double Right Coronary Artery Originating from Separate Ostia: A Report of Two Cases.

CONTEXT: Coronary artery anomalies are uncommon and most are incidental findings. Double right coronary artery (RCA) is a very rare coronary artery anomaly. CASE REPORT: We report two cases of double RCA incidentally found in electrocuted patients. Both cases showed double RCA arising from separate ostia. On microscopy, both right coronaries showed no significant pathology in the first case while in the second case, the posterior RCA showed features of obliterative arteritis. CONCLUSION: Although double coronary artery has been regarded as hemodynamically insignificant, it may be associated with atherosclerosis, acute coronary syndromes, and other anomalies. It is important to know the anatomic variants. Meticulous grossing and careful observation could unearth hidden anomalies.

Randomized Trial of Primary PCI with or without RoutineManual Thrombectomy

During primary percutaneous coronary intervention (PCI), manual thrombectomymay reduce distal embolization and thus improve microvascular perfusion. Smalltrials have suggested that thrombectomy improves surrogate and clinical outcomes,but a larger trial has reported conflicting results.MethodsWe randomly assigned 10,732 patients with ST-segment elevation myocardial infarction(STEMI) undergoing primary PCI to a strategy of routine upfront manualthrombectomy versus PCI alone. The primary outcome was a composite of deathfrom cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, orNew York Heart Association (NYHA) class IV heart failure within 180 days. The keysafety outcome was stroke within 30 days.ResultsThe primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomygroup versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in thethrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.86). Therates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone;hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.34) and the primary outcome plusstent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio,1.00; 95% CI, 0.89 to 1.14; P = 0.95) were also similar. Stroke within 30 days occurredin 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%)in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P = 0.02).ConclusionsIn patients with STEMI who were undergoing primary PCI, routine manual thrombectomy,as compared with PCI alone, did not reduce the risk of cardiovasculardeath, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heartfailure within 180 days but was associated with an increased rate of stroke within30 days. (Funded by Medtronic and the Canadian Institutes of Health Research;TOTAL ClinicalTrials.gov number, NCT01149044.

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response.

Proline-, glutamic acid- and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or γ-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression.

Endovascular coil occlusion of traumatic intradural aneurysm with presentation as carotid cavernous fistula.

Carotid cavernous fistulae (CCF) are abnormal communication between cavernous segment of the internal carotid artery and cavernous sinus. These entities are usually encountered in 0.2-0.8% of patients with traumatic skull base fractures. Traumatic cerebral aneurysms are rare and account for less than 1% of intracranial aneurysms. CCF due to ruptured intradural traumatic aneurysm is very rare and difficult to treat by surgical methods. We present one such case of a 40-year-old man with post-traumatic CCF due to a ruptured intradural aneurysm successfully treated with endovascular embolization.

Abscopal effect of low-LET γ-radiation mediated through Rel protein signal transduction in a mouse model of nontargeted radiation response.

Ascertaining the ionizing radiation (IR)-induced bystander response and its preceding molecular regulation would increase our understanding of the mechanism of acute and delayed radiobiological effects. Recent evidence clearly prompted that radiation-induced nuclear factor kappa B (NF-κB) would play a key role in bystander responses in nontargeted cells. Accordingly, we investigated the orchestration of NF-κB signaling after IR in a nontargeted distant organ. Heart tissues from C57/BL6 mice either mock irradiated or exposed (limited to lower abdomen 1 cm diameter) to single-dose IR (SDR: 2 or 10 Gy) or fractionated IR (FIR, 2 Gy per day for 5 days) were examined for onset of abscopal NF-κB signal transduction, translated activity, downstream functional signaling and associated DNA damage. Radiation significantly induced NF-κB DNA binding activity in nontargeted heart. Transcriptional profiling showed that 51, 46 and 26 of 88 genes were significantly upregulated after 2 Gy, 10 Gy and FIR. Of these genes, 22 showed dose- and fractionation-independent upregulation. Immunohistochemistry revealed a robust increase in p65 and cMyc expression in distant heart after SDR and FIR. Immunoblotting revealed increased phosphorylation of p38 after 2 Gy and extracellular signal-regulated kinases 1/2 after 10 Gy in nontargeted heart. In addition, IR exposure significantly enhanced DNA fragmentation in nontargeted heart. Together, these data clearly indicated an induced abscopal response in distant organ after clinically relevant IR doses. More importantly, the results imply that orchestration of NF-κB signal transduction in nontargeted tissues may serve as an effector and could play a key role in induced abscopal responses.

The relationship between anti-idursulfase antibody status and safety and efficacy outcomes in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with intravenous idursulfase.

In the pivotal phase II/III trial of idursulfase administered intravenously to treat mucopolysaccharidosis II, approximately half of the patients developed antibodies to idursulfase. This post-hoc analysis of data from the phase II/III trial and extension study examined the relationship between antibody status and outcomes. A total of 63 treatment-naïve patients received 0.5 mg/kg of intravenous idursulfase weekly for two years. Thirty-two patients (51%) were positive for anti-idursulfase IgG antibodies, 23 of whom (37%) became persistently positive. All patients who developed an antibody response did so by their scheduled Week 27 study visit. Positive antibody status appeared to have no statistically significant effect upon changes in six-minute walk test distance, percent predicted forced vital capacity, or liver and spleen volume. All patients showed significant decreases in urinary GAG levels, although the antibody positive group maintained somewhat higher urinary GAG levels than their antibody-negative counterparts at the end of study (138.7 vs. 94.7 µg/mg creatinine, p = 0.001). Antibody positivity was not associated with a higher event rate for serious adverse events. Among patients who had no prior infusion-related reactions, antibody positive patients were 2.3 times more likely to have a first infusion-related reaction than those who would remain negative (p = 0.017); the risk increased to 2.5 times more likely for those who were persistently positive (p = 0.009). These differences in risk disappeared among patients with a previous infusion-related reaction, likely because of preventive measures. A genotype analysis for the 36 patients with available data found that patients with nonsense or frameshift mutations may be more likely to develop antibodies, to experience infusion-related reactions, and to have a reduced uGAG response than those with missense mutations, suggesting the possibility that antibodies are not a driver of clinical outcomes but rather a marker for genotype.

Protective efficacy of Mycobacterium indicus pranii against tuberculosis and underlying local lung immune responses in guinea pig model.

Tuberculosis kills two million people each year. As the current vaccine BCG fails to prevent adult cases of TB, an improved vaccine and/or vaccination strategy is urgently needed to combat TB. Previously we reported the higher protective efficacy of Mycobacterium indicus pranii (MIP), formerly known as Mycobacterium w (M.w) as compared to BCG in murine model of TB. In this study we further evaluated the protective efficacy of MIP in guinea pig model of TB. Modulation of post infection immune response was analyzed in the lungs of MIP immunized and control groups. We found reduced bacterial loads, improved pathology and organized granulomatous response at different post infection time points in the MIP-immunized group as compared to the BCG-immunized group. Combined results suggest that MIP-immunization results in heightened protective Th1 response as compared to BCG group, early after infection with M.tb and a balanced Th1 versus immunosuppressive response at late chronic stage of infection. The study demonstrates the higher antigen presenting cells function both inside the granuloma as well as in the single cell suspension of the lung in the MIP-immunized group. We further demonstrate that live MIP is safe to use in vivo as we observed quick clearance of MIP from the body and no untoward reaction was found. Aerosol route of immunization provided higher protection. Further this study provides evidence that MIP-immunization gives significantly better long term protection as compared to BCG against TB.

Curcumin-altered p53-response genes regulate radiosensitivity in p53-mutant Ewing's sarcoma cells.

AIM: Curcumin has been demonstrated to have antitumor effects including radiosensitization by modulating many molecular targets including p53. Herein, we investigated the radiosensitizing effect of curcumin in p53 mutant Ewing's sarcoma (ES) cells. MATERIALS AND METHODS: Cells exposed to radiation with or without curcumin were examined for transcriptional and translational levels of p53 downstream targets and its influence in regulated apoptosis, DNA fragmentation, cell survival and clonal expansion. RESULTS: Curcumin significantly caused radiation induced expression of p21 and Bax, and reduced BclXl, Mcl1 with only marginal Bcl2 modulation. As a positive control to the study, both transcriptional and translational levels of p53 remained unchanged after radiation with/without curcumin. Conversely, curcumin caused radiation-induced apoptosis and DNA fragmentation. Consistently, curcumin enhanced radiation-induced cytotoxicity and clonal expansion. CONCLUSION: These results suggest that curcumin potentially radiosensitizes p53-mutant ES cells by regulating IR-modulated p53-response genes. However, the curcumin-associated p53-independent regulation of downstream targets remains to be explored.