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We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1. Our data indicate that the acquisition of resistance toward HYD1 correlates with reduced levels of the cleaved α4 integrin subunit. Consistent with reduced VLA-4 (α4β1) expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1, and the bone marrow stroma cell line HS-5. The reduction in binding of the resistant cell line to HS-5 cells translated to a compromised cell adhesion-mediated drug resistant phenotype as shown by increased sensitivity to melphalan- and bortezomib-induced cell death in the bone marrow stroma coculture model of drug resistance. Importantly, we show that HYD1 is more potent in relapsed myeloma specimens than newly diagnosed patients, a finding that correlated with α4 integrin expression. Collectively, these data indicate that this novel d-amino acid peptide may represent a good candidate for pursuing clinical trials in relapsed myeloma and in particular patients with high levels of α4 integrin. Moreover, our data provide further rationale for continued preclinical development of HYD1 and analogues of HYD1 for the treatment of multiple myeloma and potentially other tumors that home and/or metastasize to the bone. Mol Cancer Ther; 10(12); 2257–66. ©2011 AACR.

PDF file - 903K, Supplementary Figure S1: MTI-101 is more potent in U266 cell line than linear parent peptide and biotinylated peptides still retain bioactivity; Supplementary Figure S2: Biotin-HYD1 binding complex in NCI-H929 and U266 MM cell lines; Supplementary Figure S3: Overexpression of CD44s in 8226 via retroviral infection results in functional CD44; Supplementary Figure S4: Reduction in syndecan-1 expression failed to confer resistance to MTI-101 induced cell death; Supplementary Figure S5: Reduction in basigin expression failed to confer resistance to MTI-101 induced cell death; Supplementary Figure S6: MTI-101 necrotic cell death in Rip1/Rip3 and Drp1 independent in NCI-H929 cell line, but partially involved in U266; Supplementary S7: MTI-101 has activity as a single agent in 5TGM1 in vivo mouse model.

Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma cell lines. Because of the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as a single agent using two myeloma models that consider the bone marrow microenvironment. MTI-101 treatment similar to HYD1 induced reactive oxygen species, depleted ATP levels, and failed to activate caspase-3. Moreover, MTI-101 is cross-resistant in H929 cells selected for acquired resistance to HYD1. Here, we pursued an unbiased chemical biology approach using biotinylated peptide affinity purification and liquid chromatography/tandem mass spectrometry analysis to identify binding partners of MTI-101. Using this approach, CD44 was identified as a predominant binding partner. Reducing the expression of CD44 was sufficient to induce cell death in multiple myeloma cell lines, indicating that multiple myeloma cells require CD44 expression for survival. Ectopic expression of CD44s correlated with increased binding of the FAM-conjugated peptide. However, ectopic expression of CD44s was not sufficient to increase the sensitivity to MTI-101–induced cell death. Mechanistically, we show that MTI-101–induced cell death occurs via a Rip1-, Rip3-, or Drp1-dependent and -independent pathway. Finally, we show that MTI-101 has robust activity as a single agent in the SCID-Hu bone implant and 5TGM1 in vivo model of multiple myeloma. Mol Cancer Ther; 12(11); 2446–58. ©2013 AACR.

Supplementary Data from HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells

HYD1 is a D–amino acid peptide that was previously shown to inhibit adhesion of prostate cancer cells to the extracellular matrix. In this study, we show that in addition to inhibiting adhesion of multiple myeloma (MM) cells to fibronectin, HYD1 induces cell death in MM cells as a single agent. HYD1-induced cell death was necrotic in nature as shown by: (a) decrease in mitochondrial membrane potential (Δψm), (b) loss of total cellular ATP, and (c) increase in reactive oxygen species (ROS) production. Moreover, HYD1 treatment does not result in apoptotic cell death because it did not trigger the activation of caspases or the release of apoptosis-inducing factor and endonuclease G from the mitochondria, nor did it induce double-stranded DNA breaks. HYD1 did initiate autophagy in cells; however, autophagy was found to be an adaptive response contributing to cell survival rather than the cause of cell death. We were further able to show that N-acetyl-L-cysteine, a thiol-containing free radical scavenger, partially protects MM cells from HYD1-induced death. Additionally, N-acetyl-L-cysteine blocked HYD1-induced as well as basal levels of autophagy, suggesting that ROS can potentially trigger both cell death and cell survival pathways. Taken together, our data describe an important role of ROS in HYD1-induced necrotic cell death in MM cells. [Mol Cancer Ther 2009;8(8):2441–51]

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL.

Reservoir geomechanical studies play a decisive role in identifying wellbore instability and weak zones in offshore petroleum reservoirs. In this study, an integrated workflow developed with 1D Mechanical Earth Models (1D MEM), uniaxial compressive strength and swelling tests using well logs, drilling, and core data of production and exploratory wells from the North-Heera field, Mumbai offshore, India. Lithology-based correlations are utilized for calculating continuous profiles of rock mechanical properties by taking well logs as a primary source of input. Insights of fracture gradients and stresses are generated by interpretation of the pore pressure. UCS created from the well logs shows the low value of 15 MPa and high Poison's ratio of 0.38–0.45. Fracture pressure analysis of the wells specifies the lower fracture initiation pressures at 300 m are 5ppg–15ppg, which are shale and clay formation. Shale swelling tests are performed to know the hydration properties of shales present at shallow depths. The core samples' loading tests' results are very close to the UCS models constructed from the well logs. The combined analysis examines fracture pressures around wellbores, hydration of shales, weak zones identification, and wellbore instability.

Ghee (milk fat) due to its high price and demand is highly susceptible to adulteration for economic gains. Further, due to advanced practices of adulteration, its detection is becoming difficult by any single method. In the present study, methods based upon physico-chemical (BR reading and RM value) and chromatography (fatty acid, triglycerides, and plant sterols profiling) were evaluated to detect adulteration. Pure ghee was adulterated @ 1%, 2.5%, 5%, and 10% with coconut, soya bean, groundnut, and sunflower oil. Results of physico-chemical methods indicated that BR reading crossed regulatory limit only @ 10% of sunflower and soya bean oil adulteration while for the other two oils it was within the acceptable range (FSSAI standards for Gujarat i.e. 40 to 43.5). In the case of RM value, adulteration was not detected with any oil up to 10% level of adulteration with respect to FSSAI regulation (i.e. minimum 24) for Gujarat. Among chromatographic methods, fatty acids marker molecules like lauric for coconut and linoleic for soya bean, groundnut, and sunflower oil showed an increase upon adulteration even @ 1%. Marker fatty acids % values were falling outside the range for lauric (i.e.2.3 to 3.2%) and linoleic (i.e.1 to 2%) as specified by FSSAI in the manual of analysis for milk and milk products 2016 however, natural variations might affect the results. Triglyceride profiling was found to be capable of detecting adulteration @ 5% for all the oils except groundnut which was detected @ 10%. Plant sterols (â-sitosterol and stigmasterol) based method was found suitable to detect adulteration @ 1% with sunflower and soya bean oil, @ 2.5% with groundnut oil, and @ 5% with coconut oil. All the methods appear to have their strengths and limitations; hence laboratories may apply a combination of techniques to detect advanced adulteration.

Recently numerous automated microbiological methods have been developed which aims to provide accurate, precise, and rapid test results, but their performance needs to be established before being used for sample analysis. The objective of the study is to evaluate the comparison between an automated rapid technique “TEMPO” and a conventional method for enumeration of microorganisms in the Skimmed Milk Powder, Milk, Infant Milk Food and Paneer. The samples were artificially contaminated with reference microbial cultures for the study. The study was done for Total Aerobic Count as per IS 5402, enumeration of Coliform as per IS 5401 (Part-1), Yeast and Mould count as per IS 5403, and enumeration of Escherichia coli as per IS 5887 (Part-3). All samples were analyzed by both TEMPO and IS methods. The Acceptability Limit (AL) is set at ± 0.5 log10 units as per ISO 16140-2: 2016. Acceptability Limit is expressed as a difference between the reference and the alternative method. Logarithmic differences between the results obtained from two methods are d” 0.5 log for Aerobic count, Yeast and Mould count, Total Coliform count and Escherichia coli count. Statistical analysis of the results have shown good rate of agreement for all artificially contaminated samples for the two methods, when counted for Aerobic count at 30°C for 40-48 hours, Coliform count at 30°C for 24-27 hours, Yeast and Mould count at 25°C for 72-76 hours and Escherichia coli count at 37°C for 22-27 hours.

Introduction: Neoadjuvant chemotherapy followed by radical cystectomy (RC) and pelvic lymph node dissection is the standard radical management for muscle‐invasive bladder cancer (MIBC). However, major pelvic surgery is not suitable for all patients and combined modality therapy (CMT) offers an alternative for patients who want to retain their bladder. Brachytherapy (BT), as part of CMT, has been offered in selective cases of bladder cancer. Objectives: To evaluate the clinical effectiveness of BT for solitary urinary bladder tumours in terms of survival, local recurrence (LR) rates, and adverse events. Methods: A systematic review was conducted using defined search terms using online databases. Articles that discussed the use of BT as part of multi‐modality treatments for MIBC were included. Results: Searches returned 112 articles of which 20 were deemed suitable for analysis. In all, 15 of the 20 articles reported overall survival (OS) at 5 years, 2747 patients were at risk and 1670 were alive after 5 years (60%): seven studies reported OS at 10 years, with 817 patients at risk and 350 alive at 10 years (42%). Disease‐specific survival at 5 years was reported in four studies, with 371 patients at risk and 279 alive (75%) at 5 years. LR rates were reported across all 20 studies and ranged from 0% to 32%. Conclusion: Brachytherapy as part of CMT for MIBC is not a standard technique. It is an effective treatment in experienced centres for a selected patient population who wish to preserve their bladder. In such patients, CMT‐BT is well tolerated with an acceptable safety profile.

Complex surgery associated with major hemorrhage presents particular risks for Jehovah's Witnesses who do not accept transfusion of blood products. Intraoperative use of two cell saver machines simultaneously can maximize the yield of salvaged blood from both the operative field and from washed surgical swabs and can potentially be life‐saving.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Despite initial clinical responses, long‐term efficacy is not possible because of acquired resistance to these therapies. We have developed EGFR TKI drug‐tolerant (DT) human lung cancer cell lines as a model for de novo resistance. Mass spectroscopic analysis revealed that the cytochrome P450 protein, CYP51A1 (Lanosterol 14α‐demethylase), which is directly involved with cholesterol synthesis, was significantly upregulated in the DT cells. Total cellular cholesterol, and more specifically, mitochondrial cholesterol, were found to be upregulated in DT cells. We then used the CYP51A1 inhibitor, ketoconazole, to downregulate cholesterol synthesis. In both parental and DT cells, ketoconazole and EGFR TKIs acted synergistically to induce apoptosis and overcome the development of EGFR tolerance. Lastly, this combination therapy was shown to shrink the growth of tumors in an in vivo mouse model of EGFR TKI resistance. Thus, our study demonstrates for the first time that ketoconazole treatment inhibits upregulation of mitochondrial cholesterol and thereby overcomes EGFR‐TKI resistance in lung cancer cells.

MitoNEET (gene cisd1) is a mitochondrial outer membrane [2Fe-2S] protein and is a potential drug target in several metabolic diseases. Previous studies have demonstrated that mitoNEET functions as a redox-active and pH-sensing protein that regulates mitochondrial metabolism, although the structural basis of the potential drug binding site(s) remains elusive. Here we report the crystal structure of the soluble domain of human mitoNEET with a sulfonamide ligand, furosemide. Exploration of the high-resolution crystal structure is used to design mitoNEET binding molecules in a pilot study of molecular probes for use in future development of mitochondrial targeted therapies for a wide variety of metabolic diseases, including obesity, diabetes and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. MitoNEET is an iron-sulfur protein found in the outer mitochondrial membrane and implicated in several metabolic disorders. Here the crystal structure of mitoNEET with a bound sulfonamide ligand is reported and used to design new mitoNEET ligands.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC(50) value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1–induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.

Thermohaline staircases are a well-known peculiar feature of the Tyrrhenian Sea. Generated by extensive double diffusion processes fueled by lateral intrusions, they are considered to be the most stable of all the staircases that have been detected in the world ocean, seeing their persistence of more than 40 years in the literature. Double diffusion leads to efficient vertical mixing, potentially playing a significant role in guiding the diapycnal mixing. The present study investigates this process of mixing in the case of the Tyrrhenian staircases by calculating the heat and salt fluxes in their gradient zones (interfaces) and the resulting net fluxes in adjacent layers using hydrological profiles collected from 2003 to 2016 at a station in the heart of the basin interior. The staircases favor downward fluxes of heat and salt, and the results of the calculations show that these are greater where temperature and salinity gradients are also high. This condition is more frequently encountered at thin and sharp interfaces, which sometimes appear as substructures of the thicker interfaces of the staircases. These substructures are hot spots where vertical fluxes are further accentuated. Due to the increasing salt and heat content of the Levantine Intermediate Water (LIW) during the observation period, a rise in the values of the fluxes was noted in the portion of the water column below it down to about 1800 m. The data furthermore show that internal gravity waves can modulate the structure of the staircases and very likely contribute to the mixing, too, but the sampling frequency of the time series is too large to permit a proper assessment of these processes. It is shown that, at least during the period of observation, the fluxes due to salt fingers do not reach the bottom layer but remain within the staircases.

Introduction The management of recurrent non-muscle-invasive bladder cancer (NMIBC) typically requires repeated transurethral resections under general anaesthesia. This is costly and results in poor health-related quality-of-life for patients. Outpatient-based laser ablation and diathermy to recurrent tumours could reduce morbidity and cost of managing NMIBC. This systematic review evaluates the safety and efficacy of outpatient-based diathermy or laser ablation for recurrent NMIBC. Method The EMBASE, MEDLINE and Cochrane Library were searched until June 2020. All studies evaluating the use of outpatient diathermy or laser ablation for NMIBC were included. The quality of evidence and risk of bias were assessed using the GRADE and ROBINS-I tools, respectively. Results From 1328 studies identified, 17 studies (1584 patients) were included. Overall, the majority of tumours (80%) were low-grade (G1 and G2). Laser ablation and diathermy resulted in a mean recurrence rate of 47% and 40% at 20-31 months follow-up, respectively, with a mean progression rate of 3-11%. Both procedures were well-tolerated with low pain scores (mean score of 1) and low periprocedural complication rates. However, the overall quality of evidence of low. Conclusions This review demonstrates that both procedures have good short-term efficacy in patients with low-grade NMIBC. The procedures are well-tolerated with low complication rates and importantly, reduce the need for intervention under general anaesthesia. These findings can aid patient counselling regarding less invasive treatment options, avoiding the morbidity of transurethral resection. Future randomised studies with standardised risk stratification and outcome measures are required to add to the quality of evidence.

Aim Non-muscle-invasive bladder cancer (NMIBC) is the most prevalent form of bladder cancer, predominantly affecting the elderly population. The most common treatment for recurrent NMIBC is transurethral resection of the bladder tumour (TURBT), which carries a risk of perioperative morbidity and mortality in this often-co-morbid population. Outpatient laser ablation of low-grade NMIBC recurrences is a minimally invasive treatment option, but long-term efficacy is poorly reported. Method We retrospectively reviewed the case notes of all patients treated with Holmium:YAG laser ablation from 2008-2016. Data regarding patient demographics, original histology, dates of procedures, follow-up time, recurrence, progression, and complications were recorded. Results A total of 199 procedures were performed on 97 patients (mean age of 83.56), 73 (75.3%) of which originally had low-grade (G1 or G2) tumours. Overall, 55 (56.7%) patients developed tumour recurrence at long-term follow-up (mean 5.36 years), and only 9 (9.3%) patients had tumour progression to a higher stage or grade, but there was no progression to muscle-invasive disease. The median recurrence-free, progression-free and overall survival times were 1.69 years (95% CI 1.20-2.25), 5.70 years (95% CI 4.10-7.60) and 7.60 years (95% CI 4.90-8.70), respectively. No patients required emergency inpatient admission after laser ablation for any associated complications. Conclusions Office-based Holmium: YAG laser ablation is an oncologically-safe method of managing recurrent low-grade non-muscle-invasive bladder cancer in the long-term, with no patients progressing to muscle-invasive disease. Furthermore, the procedure is safe, and no significant complications were seen in this elderly and co-morbid population.

The characterization of the reservoir rock's geomechanical properties is critical to address wellbore instabilities and subsidence-related issues. To address these issues, lab-derived dynamic and static elastic properties are essential to match the in-situ rock properties. In this study, as part of a new integrated workflow P-wave and S-wave velocities are congregated using ultrasonic transducers for the core plugs, which constitutes mainly carbonates, shales, and both. Mineral composition, shale anisotropy, seismic velocities, and cross plots are studied to understand shear wave splitting. During this study, as a part of 1D mechanical Earth models, rock elastic properties are calculated for 60 wells using petrophysical logs (gamma, density, acoustic and caliper). Also, triaxial loading tests are conducted on 14 specimens collected from the same wells, static Poisson's ratio and static Young's modulus are computed from the stress-strain curves. The major differences are observed between static and dynamic elastic properties calculated from well logs and lab tests. Cohesion and friction angle for rock samples are estimated from the triaxial tests under different confining pressures. The objective of this study is to compare the elastic properties derived from the ultrasonic method with well logs and fill the gaps in the 1D geomechanical model. The combined analysis of elastic properties from different methods provides exciting insights on wellbore stability in anisotropic rock.

The subsidence of offshore wells and platforms is a profound problem in the oil and gas industry. A new approach to reservoir geomechanical studies is used to analyze wellbore instabilities and investigate the subsidence of reservoirs. This study comprises an integrated workflow for developing a 3D geomechanical earth model for the North-Heera field, India. 1D Mechanical Earth Models are constructed for 40 wells to study the wellbore instabilities of drilled wells in this region and determine the mud weight for successful drilling and completions for future developments. A 3D geomechanical model is developed by integrating geological surfaces, fault lines, wireline logs, drilling, and completion data. Heterogeneous 3D models are developed using local grid refinement by a simple kriging approach. Analyzing these models identifies that the shallow zones of depth between 300 and 1000 m have a significant spatial gradient in elastic properties. Series of triaxial loading tests are conducted on the core samples collected from different wells drilled in this block. Mohr–Coulomb's failure criteria derived from loading tests aid in determining the rock strength parameters derived from wireline logs. The combined analysis of geomechanical models and rock failure parameters derived from loading tests facilitates investigating the weak formations zones causing wellbore instability problems and subsidence in shallow depths

Bladder cancer (BC) is the 10th most common malignancy worldwide and the patient experience is found to be worse than that for patients diagnosed with other cancer types. We aimed to develop a wellbeing intervention to help improve the bladder cancer patient experience by ameliorating their health-related Quality of Life (HRQoL). We followed the 3 phases of the modified Medical Research Council (MRC) Framework for development of complex interventions. Following a systematic review of the literature on mental, sexual, and physical wellbeing, we conducted discussion groups with patients and healthcare professionals on these 3 themes. A consultation phase was then conducted with all relevant stakeholders to co-design a wellbeing intervention as part of a feasibility study. A pragmatic wellbeing feasibility trial was designed based on the hypothesis that a wellbeing program will increase patient awareness and attendance to services available to them and will better support their needs to improve HRQoL. The primary feasibility endpoints are patient attendance to the services offered and changes in HRQoL. The principle of patient centered care has strengthened the commitment to provide a holistic approach to support BC patients. In this study, we developed a wellbeing intervention in collaboration with patients and healthcare professionals to meet an unmet need in terms of the BC patient experience.

Background Upper tract urothelial carcinoma (UTUC) is a rare urological cancer that is still an important public health concern in many areas around the world. Although UTUC has been linked to a number of risk factors, to our knowledge no systematic review has been published on the overall incidence and prevalence of de-novo UTUC. This review aimed to examine the global epidemiology of UTUC to provide clinicians and public health specialists a better understanding of UTUC. Methods A systematic search was conducted on MEDLINE, Embase, and the Web of Science using a detailed search strategy. Observational epidemiological studies describing the incidence and prevalence of de-novo UTUC in adults were included, and the Joanna Briggs Institute checklist was used for critical appraisal and data extraction of the studies selected. Results The systematic search identified 3506 papers, of which 59 papers were included for qualitative synthesis. The studies selected included data ranging from the years 1943 to 2018. A comprehensive qualitative synthesis of the data was performed. UTUC incidence generally varied according to age (higher with increasing age), sex (unclear), race (unclear), calendar time (increased, stable, or decreased according to region), geographical region (higher in Asian countries), occupation (higher in seamen and printers), and other population characteristics. Prevalence was only reported by one study, which showed UTUC to have the highest incidence of the rare urogenital cancers in Europe. Conclusion This systematic review highlights an increased incidence of UTUC in certain groups, including increasing age and certain occupations such as seamen. The incidence of UTUC also varies between certain geographical regions. The trend of UTUC incidence for sex, race, and calendar time is less clear due to a wide variety of metrics used by the studies identified. More studies are also required on the prevalence of UTUC to understand its disease burden. Trial registration This review was registered on PROSPERO (registration number CRD42019134255).

Context Management of non–muscle-invasive bladder cancer (NMIBC) is costly and associated with negative health-related quality-of-life effects, in part because of the frequent need for repeated transurethral resections under general/regional anaesthesia. Outpatient-based diathermy or laser ablation is another option, but evidence for its efficacy is mixed and its use is controversial. Objective To systematically review evidence regarding the efficacy and safety of outpatient diathermy and laser ablation for the treatment of recurrent NMIBC. Evidence acquisition The EMBASE, MEDLINE/PubMed, and Cochrane Library were searched from inception to June 26, 2020. All studies evaluating the use of diathermy or laser ablation for bladder tumours (new or recurrent) in an outpatient setting under local anaesthetic were included. Two reviewers independently screened all articles, searched the reference lists of retrieved articles, and performed the data extraction. The quality of evidence and risk of bias were assessed using the GRADE and ROBINS-I tools. Evidence synthesis The search yielded 1328 studies. After excluding duplicates, 1319 titles and abstracts were screened and 17 studies (1584 patients) were eligible for inclusion in the final review. The majority of patients had small, low-grade tumours, but there was heterogeneity in the inclusion criteria. Overall, laser ablation and diathermy resulted in mean recurrence rates of 47% and 32% at follow-up of 22–38 mo, respectively, with a mean progression rate of 3–12% (low certainty of evidence). Both procedures were well tolerated, with low pain scores and low periprocedural complication rates (moderate certainty of evidence). Conclusions Outpatient diathermy and laser ablation have good short-term efficacy in patients with low-grade NMIBC and reduce the need for intervention under general/regional anaesthesia. The procedures are well tolerated with low complication rates. The overall certainty of evidence is low, with heterogeneity between studies and methodological limitations. However, we have highlighted the need for randomised trials with long-term follow-up using standardised risk classification and outcome measures. Despite these limitations, the findings will aid in patient counselling regarding this less invasive treatment option that avoids the morbidity of transurethral resection. Patient summary Outpatient diathermy and laser ablation have good success rates in treating recurrent low-grade bladder tumours in the short term, avoiding the need for more invasive procedures under general/regional anaesthesia, with low rates of side effects. Further studies are needed to determine whether these treatments remain safe and effective in the long term.

OBJECTIVES To determine if the presence of non-urothelial variant histology (NUVH) is associated with a poorer prognosis following radical cystectomy (RC) compared to pure urothelial carcinoma (PUC). PATIENTS AND METHODS A prospectively maintained database of all patients undergoing RC at a high-volume regional tertiary bladder cancer service between January 2010 and January 2017 was retrospectively analysed looking for patients with NUVH. Multivariate Cox proportional hazards regression analysis was used to determine disease recurrence, overall survival and bladder cancer-specific survival, as well as lymph node positivity. Association of tumour stage was determined using chi-squared analysis. RESULTS In total, 430 patients underwent RC of which 73 (17%) had NUVH and 357 (83%) had PUC. The median (range) follow-up was 45.0 (8.5-100.2) months. The presence of NUVH was associated with both increased overall (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.21-2.85) and bladder cancer-specific mortality (HR 1.81, 95% CI 1.91-3.01), as well as disease recurrence (HR 1.71, 95% CI 1.06-2.75) in multivariate analysis. Squamous cell variant was also associated with increased overall mortality (HR 1.91, 95% CI 1.16-3.13), cancer-specific mortality (HR 2.03, 95% CI 1.21-3.42) and disease recurrence (HR 2.08, 95% CI 1.23-3.52), although this was not seen in other variant subtypes. Lymph node positivity was not associated with NUVH in multivariate analysis (HR 1.28, 95% CI 0.59-2.75), but NUVH was associated with advanced tumour stage on chi-squared analysis (P < 0.001). CONCLUSION Our results showed a risk of shorter survival in NUVH compared to PUC. This suggests NUVH as an independent predictor of worse outcomes. As a result, patients with NUVH should be counselled preoperatively that overall and disease-specific outcomes are worse postoperatively and about the possible need for adjuvant treatment.

HYD1 is an all D-amino acid linear 10-mer peptide that was discovered by one-bead-one-compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N- and C-terminal lysine side chains were contributors to the biological activity of the linear 10-mer analogs. This observation led us to hypothesize that display of the hydrophobic pentapeptide sequence of HYD1 in a cyclic beta-hairpin-like scaffold could lead to better bioavailability and biological activity. An amphipathic pentapeptide sequence was used to form an antiparallel strand and those strands were linked via dipeptide-like sequences selected to promote β-turns. Early cyclic analogs were more active but otherwise mimicked the biological activity of the linear HYD1 peptide. The cyclic peptidomimetics were synthesized using standard Fmoc solid phase synthesis to form linear peptides, followed by solution phase or on-resin cyclization. SAR studies were carried out with an aim to increase the potency of these drug candidates for the killing of multiple myeloma cells

Background: Radical cystectomy (RC) and urinary diversion are the recommended treatment for patients with muscle invasive bladder cancer. This is complex surgery, associated with significant patient morbidity and mortality. Frailty has been shown to be an independent risk factor for adverse outcomes in several surgical populations. Preoperative assessment of frailty is advocated in current guidelines but is not yet standard clinical practice. Aims: This systematic review and narrative synthesis aims to examine whether patients undergoing RC are assessed for frailty, what tools are used, and whether an association is found between frailty and adverse outcomes in this population. Results: Nine studies, published within the last 4 years, describe the use of tools reporting to measure frailty in the RC population. All demonstrate increased risk of adverse postoperative outcomes with higher frailty levels. Only one study used a validated frailty tool. The majority of studies measure frailty using variations on a tool derived from a large database (ACS-NSQIP) effectively counting co-morbidities, rather than assessing the multidomain nature of the frailty syndrome. Conclusion: The recognition of frailty as an important consideration in the perioperative period is welcome. This systematic review and narrative synthesis demonstrates the need for collaboration in research and delivery of clinical care for older surgical patients. Such collaboration may provide clarity regarding terms such as frailty and multimorbidity, preventing the development of assessment tools inaccurately measuring these discreet syndromes interchangeably. More accurate assessment of patients in terms of frailty, multimorbidity and functional status may allow better modification and shared decision making leading to improved postoperative outcomes in older patients undergoing RC.

The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.

Background: Congenital diaphragmatic hernia is a rare condition describing a developmental defect of the diaphragm. It is managed surgically in the neonatal period by reduction of the herniated viscera followed by repair of the defect. We present a laparoscopic repair of a Bochdalek diaphragmatic hernia recurrence with retrieval and nephropexy of a migrated kidney with reduced function from its ectopic thoracic position. The complexities of managing this rare occurrence and lessons from this surgical challenge are discussed. Case Presentation: A 21-year-old primigravida presented with a 3-day history of right upper quadrant pain and increasing dyspnea. Of note, she had undergone a congenital right-sided diaphragmatic hernia repair as an infant. An MRI revealed a recurrent diaphragmatic defect with ectopic migration of the right kidney and bowel into an intrathoracic position. Due to worsening dyspnea, she underwent prompt laparoscopic repair of her recurrent diaphragmatic hernia. Subsequently, she underwent a planned cesarean section to control her intra-abdominal pressures and reduce the risk of hernia repair failure. Conclusion: Raised intra-abdominal pressures during pregnancy in patients with prior congenital hernia repair can result in recurrence and migration of peritoneal and retroperitoneal contents into the chest. In cases of renal unit migration, the primary concern must be to restore the anatomical position of a functioning kidney. Multidisciplinary specialist involvement in a tertiary referral base is crucial to an effective outcome.

Purpose We report the perioperative outcomes and complications after transition from extracorporeal urinary diversion (ECUD) to intracorporeal urinary diversion (ICUD) following robot-assisted radical cystectomy (RARC). Methods Analysis of data from a prospectively maintained institutional review board-approved database of 180 patients treated with cystectomy at our institution from April 2015 to October 2017 was performed. 127 patients underwent RARC and received an ileal conduit. Only five patients received a neobladder after RARC and were excluded from analysis. Results 68 patients had extracorporeal and 59 intracorporeal ileal conduit after RARC. There were no significant differences in patient demographics and oncological characteristics between the two groups. Of note, intracorporeal ileal conduit was associated with significantly reduced median total operative times (330 vs 375 min, p = 0.019), reduced median estimated blood loss (300 vs 425 ml, p

This paper describes a comprehensive approach to improved lithofacies characterization using the simultaneous pre-stack inversion, Bayesian classification, and multiple-point geostatistics. This integrated workflow provides an enhanced lithofacies characterization by reproducing the continuity of geological facies in the meandering-fluvial sandstone reservoir from Upper Assam, India. The simultaneous pre-stack inversion provides the rock elastic properties of the reservoir, such as P- impedance, s-impedance, density, and VP/VS ratio. Next, the probabilistic modeling approach of Baye's theorem is used to integrates seismic elastic properties with well log lithofacies identified from the cross-plot analysis for probability volumes of lithofacies. Finally, the multiple-point geostatistics based on the Single Normal equation Simulation algorithm is used to generate the improved lithofacies model by constraining of the lithofacies probability volumes (soft data) and well logging data (hard data). These results were compared with the Bayesian lithofacies classification and proved that the adopted method had successfully improved the continuation of the reservoir lithofacies by reproducing the lithofacies, hence an improvement in the reservoir characterization.

The microscale characteristics of gray and black shale samples collected from two different locations of Singrauli coalfield, Madhya Pradesh, India were investigated using scratch tester and Raman stress mapping. The failure events were analyzed for the entire scratch track. The areas of critical point were identified based on the acoustic emission, tangential force measurement along with characterization methods Scanning Electron Microscopy (SEM) and Raman spectroscopy. The SEM studies at the critical points indicate the failure in black and gray shale are completely different. The critical points are analyzed by confocal Raman spectroscopy for measuring the Raman spectral shifts and Raman stress mapping. The Raman spectra of disordered D band are used for quantifying the stress in the entire scratch track. Micro scratch test performed in different directions along with critical point regions of black and gray shale is compared. Raman spectral shifts of D band are measured and compared for the strained regions. This reveals the 2D Raman imaging of black and gray shale as a proxy for characterizing the stress inversion. Correspondingly the Raman peak intensity ratios along with full width at half maximum (FWHM) were calculated for the critical regions.

Objectives There is an increased awareness of the effect of a bladder cancer diagnosis and its treatments on the mental wellbeing of patients. However, few studies have evaluated the efficacy, feasibility and acceptability of interventions to improve this mental wellbeing. This systematic review is the first phase of the Medical Research Council Framework for developing complex interventions and provides an overview of the published mental wellbeing interventions that could be used to design an intervention specific for BC patients. Methods This review was conducted in accordance with the PRISMA guidelines in January 2019 and studies were identified by conducting searches for Medline, the Cochrane Central Register of Controlled Trials and Ovid Gateway. All included studies met the following criteria: mental wellbeing interventions of adults with medically confirmed diagnosis of any type of urological cancer, reported outcomes for specific HRQoL domains including psychological factors. The quality of evidence was assessed according to Down and Black 27-item checklist. Results A total of 15,094 records were collected from the literature search and 10 studies matched the inclusion and exclusion criteria. Of these, nine interventions were for patients with prostate cancer and one for patients with kidney cancer. No studies were found for other urological cancers. Depression was the most commonly reported endpoint measured. Of the included studies with positive efficacy, three were group interventions and two were couple interventions. In the group interventions, all showed a reduction in depressive symptoms and in the couple interventions, there was a reduction in depressive symptoms and a favourable relationship cohesion. The couple interventions were the most feasible and acceptable, but further research was required for most of the studies. Conclusion While awareness of the importance of mental wellbeing in bladder cancer patients is growing, this systematic literature review highlights the gap of feasible and acceptable interventions for this patient population.

PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B-cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP’s cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.

Background Bladder cancer (BC) treatment can have a detrimental effect on the sexual organs of patients and yet assessment of sexual health needs has been greatly overlooked for these patients compared to those who have undergone other cancer therapies. Methods This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines in July 2019. Studies were identified by conducting searches for Medline (using the PubMed interface), the Cochrane Central Register of Controlled Trials (CENTRAL) and Ovid Gateway (Embase and Ovid) using a list of defined search terms. Results 15 out of 37 studies included men only, 10 studies women only and 11 both sexes. Most participants were aged 50 to 65 years. Most studies (n = 34) focused on muscle invasive BC and only three on non-muscle invasive BC. Measurements of sexual dysfunction, including erection, ejaculation, firmness and desire, were the most commonly used measurements to report sexual health in men. In women, lubrification/dryness, desire, orgasm and dyspareunia were the most commonly reported. Twenty-one studies evaluated sexual dysfunction based on validated questionnaires, two with a non-validated questionnaire and through interviewing participants. Conclusion While recognition of the importance of the inclusion of psychometric measurements to assess sexual health is growing, there is a lack of consistent measures to assess sexual health in BC. With the focus on QoL arising in cancer survivorship, further studies are needed to develop, standardize and implement use of sexual health questionnaires with appropriate psychometrics and social measures to evaluate QoL in BC patients. Trial registration “PROSPERO does not currently accept registrations for scoping reviews, literature reviews or mapping reviews. PROSPERO is therefore unable to accept your application or provide a registration number. This decision should not stop you from submitting your project for publication to a journal.”

The failure of lung cancer treatments has been attributed mostly to the development of drug resistance, however the underlying cellular and molecular mechanisms are poorly understood. Cancer initiating stem cells (CSCs), present in tumors in a small percentage, play critical roles in the development of drug resistance, metastasis, and cancer relapse. Hence, novel treatments targeting both bulk cancer cells and CSCs are under intense investigation. Herein, we report that lung cancer cells grown on a 3D fibrous scaffold form tumoroids that resemble in vivo tumors, expand CSCs, and provide a platform to identify anti-CSC drugs. The screening of an NCI library of FDA-approved drugs using tumoroid cultures led to identification of Actinomycin D (AD) as a top CSC inhibitor. Since CSCs are mostly resident in the tumor’s inner core, AD was combined with an angiotensin receptor antagonist, Telmisartan (TS), which is known to increase drug permeability in tumors and was shown to have anti-CSC activity. Our results showed that AD + TS administered intra-tumorally was significantly more effective than either drug alone in both syngeneic and xenograft mouse models. The results of mechanistic studies revealed that CSC expansion in tumoroids was associated with activation of β catenin signaling and that AD + TS treatment reduced active β catenin levels in tumors. Together, these results establish the utility of the tumoroid culture system to expand CSCs ex vivo for targeted drug screening, to identify promising novel treatments with both anti-CSC and anti-cancer effects, and to individualize treatments for metastatic drug resistant lung cancer patients.

Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method