Urinary exosomal miRNA signature of IgA nephropathy: a case-control study.

IgA nephropathy is the most common primary glomerulonephritis worldwide and can progress to end-stage kidney disease (ESKD). The current "gold standard" for diagnosis is kidney biopsy, which is invasive and associated with morbidity. miRNAs are small, non-coding endogenous RNA that may serve as non-invasive biomarkers, and that are found in urinary exosomes. Thus far, there is a paucity of studies of the miRNA profile for the diagnosis of IgA nephropathy. Hence, we aimed to study the urinary exosomal miRNA signature of Indian patients with IgA nephropathy. Fifty biopsy-proven IgA nephropathy patients, 50 healthy controls and 25 patients with ESKD (IgA nephropathy) were recruited over 2 years (2020-2022). Urinary exosomes were isolated from which miRNA was extracted . Analysis of urinary exosomal miRNA was done using the digital multiplexed nCounter® human v3 miRNA Expression Assay which contains 799 unique miRNA barcodes. Candidate miRNAs were identified using Lasso regression and consensus clustering. The mean age of IgA nephropathy patients was 36.32 ± 3.067 years, mean creatinine was 2.26 ± 0.318 mg/dl and mean proteinuria was 2.69 ± 0.64 g/day. Compared to healthy controls, the majority (N = 150) of miRNAs were significantly downregulated. Five candidate miRNAs (hsa.miR.146b.3p, hsa.miR.599, hsa.miR.4532, hsa.miR.664b.5p and hsa.miR.221.5p) were able to differentiate between IgA nephropathy cases and controls (AUC > 0.90); the presence of all 5 was associated with 100% specificity and sensitivity for diagnosing IgA nephropathy cases. This study of Indian patients identified that there was a significant difference in the urinary exosomal miRNA profile between IgA nephropathy cases and healthy controls, suggesting that miRNAs may be valuable in the non-invasive diagnosis of IgA nephropathy.

Intraday dynamic rescheduling under patient no-shows.

Patient no-shows are a major source of uncertainty for outpatient clinics. A common approach to hedge against the effect of no-shows is to overbook. The trade-off between patient's waiting costs and provider idling/overtime costs determines the optimal level of overbooking. Existing work on appointment scheduling assumes that appointment times cannot be updated once they have been assigned. However, advances in communication technology and the adoption of online (as opposed to in-person) appointments make it possible for appointments to be flexible. In this paper, we describe an intraday dynamic rescheduling model that adjusts upcoming appointments based on observed no-shows. We formulate the problem as a Markov Decision Process in order to compute the optimal pre-day schedule and the optimal policy to update the schedule for every scenario of no-shows. We also propose an alternative formulation based on the idea of 'atomic' actions that allows us to apply a shortest path algorithm to solve for the optimal policy more efficiently. Based on a numerical study using parameter estimates from existing literature, we find that intraday dynamic rescheduling can reduce expected cost by 15% compared to static scheduling.

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation.

PURPOSE: Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation. METHODS: In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety. RESULTS: As of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. CONCLUSION: Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRASG12C-mutated solid tumors.

Investigation of the hydration process and biological activity of a novel nanosilver incorporated dicalcium silicate based retrograde filling material.

Background: Although several materials have been used for retrograde filling following apical surgeries, there is no consensus on a single best material. Tricalcium silicate-based types of cement have been developed as root-end filling materials mainly due to tricalcium silicate's hydraulic properties. However, its unfavorable setting characteristics and minimal antimicrobial properties have necessitated the introduction of new additives into the existing commercially available materials. To design an affordable product based on a dicalcium silicate with a shorter set time, minimal cytotoxic complications, and enhanced antibacterial activity, we developed a new endodontic cement from pure raw materials, intending to satisfy the prerequisites of ideal retrograde material. Methods: The composition of the experimental calcium silicate-based cement included the addition of calcium chloride and silver nanoparticles in varying concentrations. Structural characterization was carried out using energy dispersive analysis by X-rays using scanning electron microscope (EDAX SEM) and hydration characteristics were performed using an X-ray diffractometer (XRD). The experimental material was further evaluated for biocompatibility using MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)assay and antibacterial activity was evaluated using an agar diffusion test against Enterococcus faecalis. Results: The structural characterization and hydration characteristics revealed that the experimental cement was dicalcium silicate based with favorable biocompatibility and enhanced antibacterial activity. Tricalcium silicate based mineral trioxide aggregate (MTA) also had favourable biocompatibility, however, its antibacterial activity was significantly decreased when compared to the novel cement. Conclusion: All hydraulic cements that are available in the dental market are predominantly tricalcium silicate-based materials. There has been no evidence in the literature to date wherein it has been explored whether a dicalcium silicate-based hydraulic cement can solely be used in root-end cavities. The findings of the study revealed a dicalcium silicate based retrograde filling material with favourable biocompatibility exhibited immediately as well as in the set samples. Incorporation of silver nanoparticles boosted the antibacterial activity when compared to that of ProRoot MTA. This material could potentially reinstate the usual hype created with tricalcium silicate types of cement since dicalcium silicate cements also exhibit similar properties.

Apprehensions and Optimism among Dental Professionals during the COVID-19 Pandemic-A Nationwide Cross-Sectional Evaluation.

Globally, the pandemic of the coronavirus disease, which started in Wuhan, China, has become a major issue for public health. The COVID-19 epidemic notably causes health professionals to experience significantly more emotional stress than the general populace. The present study proposes to investigate the fear aspect in dentists in the initiation of clinical practice during these times. An online cross-sectional study was conducted among dental practitioners based on a pre-validated questionnaire. The data were expressed as frequency and percentage analyzed using the chi-square test using SPSS version 25. The data was obtained from 271 participants, where clinical practice after the first wave was mostly by freelancers (p-value = 0.01); most of whom were married (p-value = 0.065); 19.1% attached to institutes did not have changes in earnings; 28.1% of private practitioners had less than 10% reduction in cases. A total of 62% of private practitioners are concerned about the vaccine's preventative effects (p-value = 0.026), and 57% of private practitioners worry about being sued for the delay in treatment (p-value = 0.036). Only 33.1% of employees in institutions worry that becoming sick could endanger their family. As dentists continue to work their way through this pandemic, these pressures only occasionally have an impact on them. According to the researchers, this is the first study that has captured the anxiety and apprehensions that dental practitioners experienced during the height of the COVID-19 outbreak in India in April 2021. The study's findings demonstrate that the study population was generally upbeat and confident that they could quickly overcome their fear.

Comparative characterization and analysis of telomere length in stem cells derived from deciduous and permanent teeth.

Background: Understanding the influence of age on growth kinetics and telomere length in dental stem cells is essential for the successful development of cell therapies. Hence, the present study compared the basic cellular and phenotypical characteristics of stem cells from human exfoliated deciduous teeth (SHEDs) and dental pulp stem cells (DPSCs) of permanent teeth and their telomere lengths using quantitative real-time polymerase chain reaction. Materials and Methods: The study is an in vitro original research article. Primary cultures of SHED and DPSCs (n = 6 each) were successfully established in vitro, and the parameters analyzed were the morphology, viability, proliferation rate, population doubling time (PDT), phenotypic markers expression, and the relative telomere lengths. Data were analyzed by analysis of variance and P < 0.05 was considered statistically significant. Results: SHED and DPSCs exhibited a small spindle-shaped fibroblast-like morphology with >90% viability. The proliferation assay showed that the cells had a typical growth pattern. The PDT values of SHED and DPSCs were 29.03 ± 9.71 h and 32.05 ± 9.76 h, respectively. Both cells were positive for surface markers CD29, CD44, and CD90. However, they were negative for CD45 and human leukocyte antigen DR. Although the differences in relative telomere lengths between the individual cell lines of SHED and DPSCs were observed, no significant (P > 0.05) variations were found for the mean T/S ratios of both the cells. Conclusion: SHED and DPSCs displayed similar morphology, proliferation rates, and phenotypic features. The relative telomere lengths were slightly shorter in DPSCs than SHED, but the values were not significantly different. Thus, SHED and DPSCs can be considered as recognized sources for regenerative applications in dentistry.

Ozonated water as an irrigant in disinfecting root canal systems - a systematic review.

Aim To evaluate the efficacy of ozonated water as an irrigant in disinfection of the root canal system.Materials and methods This systematic review was conducted according to PRISMA guidelines and methodological studies were assessed through the Cochrane Risk of Bias tool. All studies on extracted human teeth using ozonated water were considered for the study, whereas ex vivo studies, studies on animal dentition and studies which were published in languages other than English were excluded from the study. The search was carried out on various databases such as PubMed, Google Scholar and ScienceDirect within the last 15 years. The assessment of quality of the studies was performed under the following: 1) size of sample; 2) control group; 3) standardisation of procedure; 4) statistical analysis performed; 5) risk of bias.Results There were a total of 154 study results, out of which duplicates and full-text analysis were excluded. A total of seven studies were included in the systematic review. The results in one study by Cardoso et al. showed ozonated water was better at reducing microbial counts, while two other studies demonstrated the difference in reducing microbial counts when comparing ozonated water against other irrigants. The remaining four studies concluded that ozonated water did not perform better as compared to the other irrigants such as sodium hypochlorite and chlorhexidine.Discussion It could be concluded that ozonated water is not a better disinfecting irrigant than sodium hypochlorite and chlorhexidine in the disinfection of the root canal system; however, it had an almost comparable level of disinfection.

Evaluation of pH, Calcium Ion Release, and Dimensional Stability of an Experimental Silver Nanoparticle-Incorporated Calcium Silicate-Based Cement.

An experimental calcium silicate-based root-end filling material incorporated with silver nanoparticles intended for use in periapical surgeries was developed with the purpose to overcome the drawbacks of existing materials and to satisfy the ideal requirements of root-end filling materials. This study was designed to evaluate the physicochemical properties, pH, calcium ion release, and dimensional stability of the experimental cement, and compare the results with commercially available ProRoot MTA (Dentsply). An independent sample test was used to analyze the data. Mean initial pH (immediately after mixing) of the experimental cement was 10.42 ± 0.04 which was higher than that of MTA. However, there was a significant increase in pH of MTA at 1 day, 2 days, and 7 days. Presence of calcium chloride favored the release of calcium ions which was significantly increased in the experimental group at 24 hours. At the end of 30 days, MTA showed a significant expansion when compared to the experimental cement (p < 0.001). In conclusion, the experimental nanoparticle-incorporated calcium silicate-based cement showed clinically acceptable physicochemical properties.

Three-dimensional semi-automated volumetric assessment of the pulp space of teeth following regenerative dental procedures.

The volumetric change that occurs in the pulp space over time represents a critical measure when it comes to determining the secondary outcomes of regenerative endodontic procedures (REPs). However, to date, only a few studies have investigated the accuracy of the available domain-specialized medical imaging tools with regard to three-dimensional (3D) volumetric assessment. This study sought to compare the accuracy of two different artificial intelligence-based medical imaging programs namely OsiriX MD (v 9.0, Pixmeo SARL, Bernex Switzerland, https://www.osirix-viewer.com ) and 3D Slicer ( http://www.slicer.org ), in terms of estimating the volume of the pulp space following a REP. An Invitro assessment was performed to check the reliability and sensitivity of the two medical imaging programs in use. For the subsequent clinical application, pre- and post-procedure cone beam computed tomography scans of 35 immature permanent teeth with necrotic pulp and periradicular pathosis that had been treated with a cell-homing concept-based REP were processed using the two biomedical DICOM software programs (OsiriX MD and 3D Slicer). The volumetric changes in the teeth's pulp spaces were assessed using semi-automated techniques in both programs. The data were statistically analyzed using t-tests and paired t-tests (P = 0.05). The pulp space volumes measured using both programs revealed a statistically significant decrease in the pulp space volume following the REP (P < 0.05), with no significant difference being found between the two programs (P > 0.05). The mean decreases in the pulp space volumes measured using OsiriX MD and 3D Slicer were 25.06% ± 19.45% and 26.10% ± 18.90%, respectively. The open-source software (3D Slicer) was found to be as accurate as the commercially available software with regard to the volumetric assessment of the post-REP pulp space. This study was the first to demonstrate the step-by-step application of 3D Slicer, a user-friendly and easily accessible open-source multiplatform software program for the segmentation and volume estimation of the pulp spaces of teeth treated with REPs.

Knowledge, attitude and practice of dental students and practitioners during the early days of COVID-19 pandemic in India: A cross-sectional study.

AIM: The novel coronavirus disease-2019 (COVID-19) is a major health problem and has affected innumerable people around the world. The current online-based study was conducted to assess the knowledge, attitude and practice (KAP) of dental students and professionals during the early days of lockdown in India from 2 April to 1 May 2020. METHODOLOGY: An online-based cross-sectional study was undertaken through WhatsApp messenger and e-mail groups among dental students and professionals. The KAP on COVID-19 was ascertained using an investigator designed and validated questionnaire. The results were stratified based on student vs professionals. The data were expressed as frequency and percentage analysed using the chi-square/Fishers exact test using IBM version 17. A probability value of <.05 was considered significant. RESULTS: A total of 287 complete responses from the dental students and professionals were received. The results indicated that the knowledge of both dental students and professionals were good and that the attitude and practice were in accordance with good clinical practice. No significant differences were found within the domains of KAP scores among the dental students and practitioners indicating that the study participants were abreast with the recent advances. CONCLUSION: The results of this study conducted during the early stage of the lockdown indicated that the dental students and professionals who had filled the questionnaire had very good knowledge of coronavirus and COVID-19. CLINICAL IMPLICATIONS: The results of the study indicate that the volunteers had good knowledge, attitude and self-care practice, which are necessary in preventing the spread of COVID-19. It is anticipated that detailed hands-on training in practical aspects of good clinical practice with protective gears will help students and professionals perform the necessary dental procedures in accordance with the guidelines set by Centers for Disease Control and Prevention and World Health Organization.

Does CT help in reducing RT-PCR false negative rate for COVID-19?

BACKGROUND: Early detection is the key to contain the ongoing pandemic. The current gold standard to detect SARS CoV2 is RT-PCR. However, it has a high false negative rate and long turnaround time. PURPOSE: In view of the high sensitivity of CT in detection of lower respiratory tract pathologies, a study of 2581 patients comparing RT-PCR status with CT findings was undertaken to see if it augments the diagnostic performance. MATERIALS AND METHODS: A multi centre prospective study of consecutive cases was conducted. All CT studies suggestive of COVID 19 pneumonia were collated and evaluated independently by three Radiologists to confirm the imaging diagnosis of COVID-19 pneumonia. The RT-PCR values were retrospectively obtained, based on the RT-PCR values, CT studies were categorised into three subgroups, positive, negative and unknown. CT features from all three groups were compared to evaluate any communality or discordance. RESULTS: Out of the 2581 patients with positive CT findings for COVID pneumonia, 825 were females and 1,756 were males in a wide age group of 28-90 years. Predominant CT features observed in all the subgroups were Ground glass densities 94.8%, in mixed distribution (peripheral and central) (59.12%), posterior segments in 92% and multilobar involvement in 70.9%. The CT features across the three subgroups were statistically significant with a P value <0.001. CONCLUSION: There was a communality of CT findings regardless of RT-PCR status. In a pandemic setting ground glass densities in a subpleural, posterior and basal distribution are indicative of COVID 19. Thus CT chest in conjunction to RT PCR augments the diagnosis of COVID 19 pneumonia; utilization of CT chest may just be the missing link in closing this pandemic.

Where have all the diseases gone during the COVID-19 pandemic?

This article focuses on a marked drop in volumes in the lockdown period during the COVID-19 pandemic across all modalities X-ray, sonography, CT scan and MRI scans and compares the volumes of data between a private and public hospital in Mumbai. This trend has been witnessed globally also. Even with easing of lockdown this has not reflected in an increase in numbers. Imaging volumes of a 1900-bed public hospital and a 220-bed private hospital in Mumbai were collated for all modalities, i.e., X-ray, sonography, CT and MRI for the months January, February 2020- Prelockdown, March 2020 Peri-lockdown, April, May 2020- Lockdown, June Unlock 1.0, July Unlock 2.0. The imaging volumes during lockdown, Unlock, were compared with prelockdown values. It was initially felt that this was due to a fear of visiting hospitals that are considered hotbeds of SARS-CoV-2. However, the same status has persisted over the 2 months of lockdown and the 2 months of unlocking. What is the cause of this huge drop in imaging volumes?

The "Butterfly Effect" and Its Correlation to the Direction of the Fracture Line in Root Dentin.

INTRODUCTION: The butterfly effect is an optical phenomenon and is related to the presence of sclerotic dentin in the roots. The unique pattern of sclerotic dentin formation produces a characteristic butterfly shape in transverse sections of the roots. The objective of this study was to evaluate the direction of the fracture line in roots that exhibit the butterfly effect. METHODS: Thirty single-rooted premolars with oval-shaped roots were decoronated and embedded in acrylic blocks and subjected to vertical force under a universal testing machine (HPBSD; Tec-Sol India, Chennai, India). Fractured roots were examined under a stereomicroscope (Model no. 080772; Lawrence and Mayo, Mumbai, India) at ×10 magnification to determine the location and direction of the fracture line. To evaluate the correlation between the direction of sclerotic dentin and the direction of the fracture line, teeth were sectioned and observed under a stereomicroscope at ×20 and ×40 magnification. The correlation was analyzed using the Fisher exact test (P < .05 for the coronal and apical thirds and P > .05 for the middle third). RESULTS: Sclerotic dentin was observed more in the apical area and less in the coronal third of the root. The correlation between the direction of sclerotic dentin and the direction of the fracture line was statistically significant in the coronal and apical thirds of the root. CONCLUSIONS: The vertical root fracture that runs buccolingually is correlated to the harder sclerotic dentin present in the mesiodistal direction.

Three-dimensional qualitative and quantitative analyses of the effect of periradicular lesions on the outcome of regenerative endodontic procedures: A prospective clinical study.

OBJECTIVES: Qualitative and quantitative evaluation of the outcomes of regenerative endodontic procedure (REP) on human immature necrotic teeth with apical periodontitis using cone-beam computed tomography (CBCT) MATERIALS AND METHODS: Immature permanent teeth (n = 50) with necrotic pulp and periradicular pathosis were treated with a cell-homing concept-based REP. Following the procedure, a limited field-of-view CBCT scan was obtained. At each recall session (6, 12, 18 months), clinical tests were performed, and a digital periapical radiograph was taken. When significant radiographic changes were evident in the follow-up, a final CBCT scan was taken for qualitative and quantitative assessment. These initial and follow-up CBCT scans were assessed for quantification of changes in root length, pulp space diameter and periradicular lesion size. The data were statistically analysed using t test, one-way ANOVA, post hoc test and paired t test (P = 0.05). RESULTS: Of the teeth, 94.6% were clinically successful based on the lack or regression of signs and symptoms after 48 months follow-up. REP resulted in a statistically significant increase in root length, decrease in pulp space diameter and periradicular radiolucency (P < 0.05). CBCT images illustrated various patterns of root maturation including an increased thickening of the canal walls and continued root maturation (37.1%), continued root development with the apical foramen remaining open (57.1%), severe calcification (obliteration) of the canal space (2.9%) and hard tissue barrier formation in the canal space between the coronal plug and the root apex (2.9%). CONCLUSION: This study highlighted that the expected outcome of radiographic root development was less predictable when immature permanent teeth with periradicular pathosis were treated with REP. CLINICAL RELEVANCE: The size and extent (expansion/destruction of the cortical plate) of periradicular lesions and abscesses influence the outcome of REP. These factors must be taken into consideration during treatment planning.

Ordering sequential competitions to reduce order relevance: Soccer penalty shootouts.

In sequential competitions, the order in which teams take turns may have an impact on performance and the outcome. Previous studies with penalty shootouts have shown mixed evidence of a possible advantage for the first shooting team. This has led to some debate on whether a change in the rules of the game is needed. This work contributes to the debate by collecting an extensive dataset of shootouts which corroborates an advantage for the first shooter, albeit with a smaller effect than what has been documented in previous research. To evaluate the impact of alternative ordering of shots, we model shootouts as a probability network, calibrate it using the data from the traditional ordering, and use the model to conduct counterfactual analysis. Our results show that alternating the team that shoots first in each round would reduce the impact of ordering. These results were in part developed as supplement to field studies to support the International Football Association Board's (IFAB) consideration of changing the shooting order.

Systemic Treatment for Squamous Cell Carcinoma of the Head and Neck.

In patients with locally advanced squamous cell cancer of the head and neck, a multimodality treatment approach is recommended. The addition of platinum-based systemic therapy concurrently with radiation has been shown to be superior to radiation alone and is considered standard therapy for locally advanced disease. No study has shown superiority of induction therapy followed by chemoradiotherapy versus chemoradiotherapy alone. In the adjuvant setting only patients with nodal extracapsular extension or positive margins seem to benefit from chemoradiotherapy versus radiotherapy alone. In the recurrent or metastatic setting, systemic treatment with chemotherapy is palliative. A subset of patients treated with PD-1 immunotherapy may achieve durable responses.

Outcomes of Patients With Metastatic Non-Clear-Cell Renal Cell Carcinoma Treated With Pazopanib.

BACKGROUND: Pazopanib is associated with increased progression-free survival (PFS) in clear-cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non-clear-cell RCC, but data on outcomes in this setting are limited. PATIENTS AND METHODS: We conducted a retrospective data analysis of records of consecutive metastatic non-clear-cell RCC patients who received pazopanib in front-line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan-Meier methods. RESULTS: Twenty-nine patients were identified with non-clear-cell metastatic RCC, 9 received pazopanib in the front-line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7-NA [not available]) in the front-line group, and 4 months (95% CI, 2.1-9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2-NA) in the front-line group, and 13.6 months (95% CI, 6.4-NA) in the salvage group. CONCLUSION: Pazopanib showed efficacy in patients with metastatic non-clear-cell RCC in the front-line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanib's role in non-clear-cell RCC in terms of efficacy and safety.

Hepatoma-derived growth factor: A survival-related protein in prostate oncogenesis and a potential target for vitamin K2.

Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor, which has previously been shown to be expressed in a variety of cancers. HDGF overexpression has also previously been correlated with a poor prognosis in several cancers. The significance of HDGF in prostate cancer, however, has not been investigated. Here, we show that HDGF is overexpressed in both androgen-sensitive LNCaP cells and androgen-insensitive DU145, 22RV1, and PC-3 cells. Forced overexpression enhanced cell viability of RWPE-1 cells, whereas HDGF knockdown reduced cell proliferation in human prostate cancer cells. We also show that HDGF may serve as a survival-related protein as ectopic overexpression of HDGF in RWPE cells up-regulated the expression of antiapoptosis proteins cyclin E and BCL-2, whereas simultaneously down-regulating proapoptotic protein BAX. Western blot analysis also showed that HDGF overexpression modulated the activity of phospho-AKT as well as NF-kB, and these results correlated with in vitro migration and invasion assays. We next assessed the therapeutic potential of HDGF inhibition with a HDGF monoclonal antibody and vitamin k2, showing reduced cell proliferation as well as inhibition of NF-kB expression in HDGF overexpressed RWPE cells treated with a HDGF monoclonal antibody and vitamin K2. Collectively, our results suggest that HDGF is a relevant protein in prostate oncogenesis and may serve as a potential therapeutic target in prostate cancer.

Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a single institution experience.

OBJECTIVE: To explore the efficacy and safety of pazopanib in a 'real-world' setting in unselected patients, as data regarding unselected patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line pazopanib are limited. PATIENTS AND METHODS: We reviewed records of patients with metastatic ccRCC treated with first-line pazopanib from 1 November 2009 through to 1 November 2012. Cox models were fitted to evaluate the association of progression-free survival (PFS) and overall survival (OS) with patient co-variables. RESULTS: In all, 88 patients were identified; 74 were evaluable for response: two (3%) had a complete response, 27 (36%) a partial response, 36 (49%) had stable disease and nine (12%) had progressive disease. The median PFS was 13.7 months [95% confidence interval (CI) 8.7-18.3]. PFS was correlated with a Karnofsky Performance Status score of <80 [hazard ratio (HR) 3.26, P < 0.001] and serum lactate dehydrogenase of >1.5 × upper limit of normal (HR 3.25, P = 0.014). The median OS was 29.1 months (95% CI 20.2-not reached). The OS was correlated with brain metastasis (HR 2.55, P = 0.009), neutrophilia (HR 1.179, P = 0.018), and anaemia (HR 3.51, P < 0.001). There were no treatment-related deaths. In all, 53 patients received second-line therapy [vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in 22 patients, mammalian target of rapamycin inhibitors (mTORi) in 22 patients, and other therapy in nine patients]; the median PFS was 8.6 months (95% CI 3.3-25.7) with VEGFR-TKI and 5 months (95% CI 3.5-15.2) with mTORi (P = 0.41); the median OS was 19.9 months (95% CI 12.9-not reached) and 14.2 months (95% CI 8.1-not reached), from initiation of second-line VEGFR-TKI or mTORi, respectively (P = 0.37). CONCLUSIONS: In this retrospective study, first-line pazopanib confirmed its efficacy in metastatic ccRCC. Trends for longer PFS and OS were seen with VEGFR-TKI compared with mTORi after first-line pazopanib.