A new class of β-aryloxyquinolines
3a–
i and their pyrano3,2-
cchromene derivatives
6a–
r incorporating a validated molecular target has been synthesized
via a nucleophilic displacement and a one-pot ...multicomponent reaction respectively.
In vitro antimicrobial activity of the synthesized compounds were investigated against a representative panel of pathogenic strains specifically
Bacillus subtilis,
Clostridium tetani,
Streptococcus pneumoniae,
Escherichia coli,
Salmonella typhi,
Vibrio cholera,
Aspergillus fumigatus and
Candida albicans. Compounds
3c,
3e,
3g,
6f,
6l and
6q exhibited excellent antibacterial activity while compound
6p exhibited more potent antifungal activity than that of first line standard drugs.
In vitro antituberculosis activity was evaluated against
Mycobacterium tuberculosis H37Rv and compound
6f is emerged as the promising antimicrobial member with better antitubercular activity. Majority of the compounds appears to be better antimicrobials but poor antituberculars.
A series of β-aryloxyquinolines
3a–
3i and their pyrano3,2-
cchromene derivatives
6a–
6r have been synthesized and compared pharmacologically concerning their antimicrobial activities as well as antituberculosis activity against H37Rv.
Display omitted
► A series of β-aryloxyquinolines
3a–
3i and their pyrano3,2-
cchromene derivatives
6a–
6r have been synthesized and compared pharmacologically concerning their antimicrobial activities as well as antituberculosis activity against H37Rv.
Background
To investigate the trends in urinary diversion (UD) in Australia over the past 20 years, to correlate with patient demographics and to compare with international data.
Methods
A ...retrospective analysis of Medicare Australia data was performed using the relevant Medicare Benefit Schedule procedure codes over the past 20 years. Included diversion procedures were ureterocutaneous, ureterocolonic, intestinal conduit and continent reservoir. All patients aged older than 15 years were included in the analyses.
Results
Over the past two decades, 6124 cystectomies and 7166 UDs were subsidized by Medicare Australia. The median age group for UD was 65–74 years old and 71.8% were male. Intestinal conduit accounted for the majority of UDs (84.9%), followed by continent reservoirs (11.8%). Ureterocolonic and ureterocutaneous accounted for small proportions (2.9% and 0.4%, respectively). The absolute numbers of UD procedures increased over the past 20 years but the proportion of different methods remained constant. The rates of continent reservoir UD were significantly higher in men and people aged less than 55 years old (P < 0.001 for both). Over the course of the study, the proportion of people aged greater than 75 years undergoing UD increased significantly (P < 0.001).
Conclusion
In contrast to major international academic institutions, the proportion of continent reservoir UDs performed in Australia has not changed over the past two decades. Intestinal conduit remains the most common UD procedure.
Over the last two decades, the annual number of cystectomies and urinary diversion procedures performed in Australia has been steadily rising. In contrast to major international academic institutions and despite increased experience, the incidence of continent urinary diversion has not increased.
Targeting PI3 kinase in cancer Bauer, Todd M; Patel, Manish R; Infante, Jeffrey R
Pharmacology & therapeutics (Oxford)
146
Journal Article
Recenzirano
The PI3K/Akt/mTOR pathway is the most frequently known activated aberrant pathway in human cancers. Pathologic activation can occur at multiple levels along the signaling pathway by a variety of ...mechanisms, including point mutations, amplifications, and inactivation of tumor suppressor genes. This pathway is also a known resistance pathway, as it can be activated by both receptor tyrosine kinases and other oncogenes. mTOR inhibitors were the first targeted molecules in this pathway, and have already been FDA-approved in multiple indications. Because of the broad potential applications of inhibiting this pathway upstream of mTOR, multiple compounds targeting PI3K are in development. In this review, we discuss the clinical development of these inhibitors, including dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-selective PI3K inhibitors. Common adverse events, including rash, nausea, vomiting, diarrhea, and hyperglycemia, have created a narrow therapeutic window for all classes of PI3K inhibitors. Furthermore, single agent clinical activity has also been limited, with the exception of isoform-selective inhibitors, particularly the PI3Kδ and PI3Kγ inhibitors in hematologic malignancies. The future role of inhibitors of the PI3K/Akt/mTOR pathway in the clinical practice of oncology likely depends on the development of patient selection strategies and the results of combination trials that are currently ongoing.
Reactive oxygen or nitrogen species are generated in the plant cell during the extreme stress condition, which produces toxic compounds after reacting with the organic molecules. The ...glutathione-S-transferase (GST) enzymes play a significant role to detoxify these toxins and help in excretion or sequestration of them. In the present study, we have cloned 1023 bp long promoter region of tau class GST from an extreme halophyte Salicornia brachiata and functionally characterized using the transgenic approach in tobacco. Computational analysis revealed the presence of abiotic stress responsive cis-elements like ABRE, MYB, MYC, GATA, GT1 etc., phytohormones, pathogen and wound responsive motifs. Three 5'-deletion constructs of 730 (GP2), 509 (GP3) and 348 bp (GP4) were made from 1023 (GP1) promoter fragment and used for tobacco transformation. The single event transgenic plants showed notable GUS reporter protein expression in the leaf tissues of control as well as treated plants. The expression level of the GUS gradually decreases from GP1 to GP4 in leaf tissues, whereas the highest level of expression was detected with the GP2 construct in root and stem under control condition. The GUS expression was found higher in leaves and stems of salinity or osmotic stress treated transgenic plants than that of the control plants, but, lower in roots. An efficient expression level of GUS in transgenic plants suggests that this promoter can be used for both constitutive as well as stress inducible expression of gene(s). And this property, make it as a potential candidate to be used as an alternative promoter for crop genetic engineering.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To externally validate and compare the performance of the European Randomized Study of Screening for Prostate Cancer risk calculator 3/4 (ERSPC‐RC3/4), the Prostate Biopsy Collaborative ...Group risk calculator (PBCG‐RC) and the van Leeuwen model to determine which prediction model would perform the best in a contemporary Australian cohort undergoing transperineal (TP) biopsy.
Materials and Methods
A retrospective review identified all patients undergoing TP biopsy across two centres. Of the 797 patients identified, 373 had the data required to test all three risk calculators. The probability of high‐grade prostate cancer, defined as International Society of Urological Pathology Grade Group >1, was calculated for each patient. For each prediction model discrimination was assessed using area under the receiver‐operating characteristic curve (AUC), calibration using numerical and graphical summaries, and net benefit using decision curve analysis.
Results
Assessment of model discrimination for detecting high‐grade prostate cancer showed AUCs of 0.79 (95% confidence interval CI 0.74–0.84) for the ERSPC‐RC3/4, 0.81 (95% CI 0.77–0.86) for the van Leeuwen model, and 0.68 (95% CI 0.63–0.74) for the PBCG‐RC, compared to 0.58 (95% CI 0.52–0.65) for prostate‐specific antigen alone. The ERSPC‐RC3/4 was the best calibrated in the moderate‐risk range of 10–40%, whilst the van Leeuwen model was the best calibrated in the low‐risk range of 0–10%. The van Leeuwen model demonstrated the greatest net benefit from 10% risk onwards, followed closely by the ERSPC‐RC3/4 and then the PBCG‐RC.
Conclusion
The ERPSC‐RC3/4 demonstrated good performance and was comparable to the van Leeuwen model with regard to discrimination, calibration and net benefit for an Australian population undergoing TP prostate biopsy. It is one of the most accessible risk calculators with an easy‐to‐use online platform, therefore, we recommend that Australian urologists use the ERSPC‐RC3/4 to predict risk in the clinical setting.
Objectives
To describe our robot‐assisted nephroureterectomy (RNU) technique for benign indications and RNU with en bloc excision of bladder cuff (BCE) and lymphadenectomy (LND) for malignant ...indications using the da Vinci Si® and da Vinci Xi robotic platform, with its pros and cons. The port placement described for Si can be used for standard and S robotic systems. This is the first report in the literature on the use of the da Vinci Xi robotic platform for RNU.
Patients and Methods
After a substantial experience of RNU using different da Vinci robots from the standard to the Si platform in a single‐docking fashion for benign and malignant conditions, we started using the newly released da Vinci Xi robot since 2014. The most important differences are in port placement and effective use of the features of da Vinci Xi robot while performing simultaneous upper and lower tract surgery. Patient positioning, port placement, step‐by‐step technique of single docking RNU‐LND‐BCE using the da Vinci Si and da Vinci Xi robot are shown in an accompanying video with the goal that centres using either robotic system benefit from the hints and tips. The first segment of video describes RNU‐LND‐BCE using the da Vinci Si followed by the da Vinci Xi to highlight differences. There was no need for patient repositioning or robot re‐docking with the new da Vinci Xi robotic platform.
Results
We have experience of using different robotic systems for single docking RNU in 70 cases for benign (15) and malignant (55) conditions. The da Vinci Xi robotic platform helps operating room personnel in its easy movement, allows easier patient side‐docking with the help of its boom feature, in addition to easy and swift movements of the robotic arms. The patient clearance feature can be used to avoid collision with the robotic arms or the patient's body. In patients with challenging body habitus and in situations where bladder cuff management is difficult, modifications can be made through reassigning the camera to a different port with utilisation of the retargeting feature of the da Vinci Xi when working on the bladder cuff or in the pelvis. The vision of the camera used for da Vinci Xi was initially felt to be inferior to that of the da Vinci Si; however, with a subsequent software upgrade this was much improved. The base of the da Vinci Xi is bigger, which does not slide and occasionally requires a change in table placement/operating room setup, and requires side‐docking especially when dealing with very tall and obese patients for pelvic surgery.
Conclusions
RNU alone or with LND‐BCE is a challenging surgical procedure that addresses the upper and lower urinary tract simultaneously. Single docking and single robotic port placement for RNU‐LND‐BCE has evolved with the development of different generations of the robotic system. These procedures can be performed safely and effectively using the da Vinci S, Si or Xi robotic platform. The new da Vinci Xi robotic platform is more user‐friendly, has easy installation, and is intuitive for surgeons using its features.
Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. ...Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors RECIST version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.
Heavy metals are common pollutants of the coastal saline area and Salicornia brachiata an extreme halophyte is frequently exposed to various abiotic stresses including heavy metals. The SbMT-2 gene ...was cloned and transformed to tobacco for the functional validation. Transgenic tobacco lines (L2, L4, L6 and L13) showed significantly enhanced salt (NaCl), osmotic (PEG) and metals (Zn++, Cu++ and Cd++) tolerance compared to WT plants. Transgenic lines did not show any morphological variation and had enhanced growth parameters viz. shoot length, root length, fresh weight and dry weight. High seed germination percentage, chlorophyll content, relative water content, electrolytic leakage and membrane stability index confirmed that transgenic lines performed better under salt (NaCl), osmotic (PEG) and metals (Zn++, Cu++ and Cd++) stress conditions compared to WT plants. Proline, H2O2 and lipid peroxidation (MDA) analyses suggested the role of SbMT-2 in cellular homeostasis and H2O2 detoxification. Furthermore in vivo localization of H2O2 and O2-; and elevated expression of key antioxidant enzyme encoding genes, SOD, POD and APX evident the possible role of SbMT-2 in ROS scavenging/detoxification mechanism. Transgenic lines showed accumulation of Cu++ and Cd++ in root while Zn++ in stem under stress condition. Under control (unstressed) condition, Zn++ was accumulated more in root but accumulation of Zn++ in stem under stress condition suggested that SbMT-2 may involve in the selective translocation of Zn++ from root to stem. This observation was further supported by the up-regulation of zinc transporter encoding genes NtZIP1 and NtHMA-A under metal ion stress condition. The study suggested that SbMT-2 modulates ROS scavenging and is a potential candidate to be used for phytoremediation and imparting stress tolerance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The management of testicular cancer has evolved over time with multimodal therapy. Retroperitoneal lymph node dissection (RPLND), which is a complex and potentially morbid treatment option, remains ...the mainstay in surgical treatment. This article reviews the surgical template, approach and anatomical considerations with regards to nerve spare in RPLND.
The standard full bilateral RPLND template has evolved over time to include the area between the renal hilum, bifurcation of the common iliac vessels, and the ureters. Morbidity with regards to ejaculatory dysfunction has led to further refinements in this procedure. Advancements in anatomical understanding of the retroperitoneal structures and their relationship to the sympathetic chain and hypogastric plexus has allowed for modification of surgical templates. Further refinements in surgical nerve sparing techniques have improved functional outcomes without sacrificing oncological outcomes. Finally, extraperitoneal access to the retroperitoneum and minimally invasive platforms have been implemented to further reduce morbidity.
RPLND requires strict adherence to oncological surgical principles regardless of template, approach and technique. Contemporary evidence shows that outcomes are best for advanced testis cancer patients when managed at high volume tertiary care facilities with surgical expertise and access to multidisciplinary care.
Summary Background Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody–drug conjugate ...containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). Methods In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1–2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m2 . Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov , number NCT01290549. Findings Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3–4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3–4 adverse events were neutropenia (18 40% of 45), anaemia (five 11%), and peripheral sensory neuropathy (four 9%). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3–4 adverse event, with neutropenia (five 56%), anaemia (two 22%), and febrile neutropenia (two 22%) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients two treatment related, and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Interpretation Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Funding Genentech.
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