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Angola forum 2022: Prospects for Angola's social and economic future

Angola forum 2022: Prospects for Angola's social and economic future 15 December 2022 — 1:00PM TO 4:30PM Anonymous (not verified) 28 November 2022 Online

At this online Angola forum, experts will discuss Angola’s social and economic future, and what to expect from 2023.

At this virtual Angola Forum, speakers will discuss Angola’s social and economic future and what to expect from 2023.

Angola experienced positive economic momentum in 2022 allowing it to exit its six-year recession, with the economy taking centre stage in the August national multiparty elections. Increased oil prices and high levels of production have driven Angola’s economic growth and improved macroeconomic conditions, as well as helping the country to reduce its public debt to 56.5 per cent of Gross Domestic Product (down from 79.7 per cent in 2021).

However, a global economic downturn in 2023, with increased inflation, means Angola’s re-elected MPLA government will need to focus on job creation, greater economic inclusivity and diversifying away from an oil-led economy. It will also require Angola to navigate its international partnerships more effectively in this era of heightened geopolitical rivalries.  

At this online Angola forum, experts will discuss Angola’s social and economic future and what to expect from 2023. Speakers will reflect on the social and economic trends seen in 2021-22 and explore election trends, human rights and international relations.

This Angola Forum is supported by the Konrad-Adenauer-Stiftung.




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Endovascular treatment for acute ischaemic stroke in routine clinical practice: prospective, observational cohort study (MR CLEAN Registry)




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Composite Prediction Score to Interpret Bone Focal Uptake in Hormone-Sensitive Prostate Cancer Patients Imaged with [18F]PSMA-1007 PET/CT

Unspecific bone uptake (UBU) related to [18F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [18F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [18F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUVmax, SUVmean, PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HUmean) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less (n = 2) or more (n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake (n = 178) as PCa metastases or not. Results: In total, 448 bone [18F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT (P < 0.001) with determination of SUVmax (P < 0.001) and HUmean (P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation (n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score’s AUC was significantly higher than that of HUmean (AUC, 0.62) and remained high among lesions with HUmean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [18F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging.




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Clinical Factors That Influence Repeat 68Ga-PSMA-11 PET/CT Scan Positivity in Patients with Recurrent Prostate Cancer Under Observation After a Negative 68Ga-PSMA-11 PET/CT Scan: A Single-Center Retrospective Study

This analysis aimed to identify clinical factors associated with positivity on repeat 68Ga-PSMA-11 PET/CT after a negative scan in patients with recurrent prostate cancer (PCa) under observation. Methods: This single-center, retrospective analysis included patients who underwent at least 2 68Ga-PSMA-11 PET/CT scans (PET1 and PET2) at UCLA between October 2016 and June 2021 for recurrent PCa with negative PET1 and no PCa-related treatments between the 2 scans. Using Prostate Cancer Molecular Imaging Standardized Evaluation criteria to define negative and positive scans, the final cohort was divided into PET2-negative (PET2-Neg) and PET2-positive (PET2-Pos). The same PET1 was used twice in the more than 2 PET cases with inclusion criteria fulfilled. Patient characteristics and clinical parameters were compared between the 2 cohorts using Mann–Whitney U test and Fisher exact test. Areas under the curve (AUCs) of the receiver operating characteristic and the Youden index were computed to determine the discrimination ability of statistically significant factors and specific cut points that maximized sensitivity and specificity, respectively. Results: The final analysis included 83 sets of 2 PET/CT scans from 70 patients. Thirty-nine of 83 (47%) sets were PET2-Neg, and 44 of 83 (53%) sets were PET2-Pos. Prostate-specific antigen (PSA) increased from PET1 to PET2 for all 83 (100%) sets of scans. Median PSA at PET1 was 0.4 ng/mL (interquartile range, 0.2–1.0) and at PET2 was 1.6 ng/mL (interquartile range, 0.9–3.8). We found higher serum PSA at PET2 (median, 1.8 vs. 1.1 ng/mL; P = 0.015), absolute PSA difference (median, 1.4 vs. 0.7 ng/mL; P = 0.006), percentage of PSA change (median, +270.4% vs. +150.0%: P = 0.031), and median PSA velocity (0.044 vs. 0.017 ng/mL/wk, P = 0.002) and shorter PSA doubling time (DT; median, 5.1 vs. 8.3 mo; P = 0.006) in the PET2-Pos cohort than in the PET2-Neg cohort. Receiver operating characteristic curves showed cutoffs for PSA at PET2 of 4.80 ng/mL (sensitivity, 34%; specificity, 92%; AUC, 0.66), absolute PSA difference of 0.95 ng/mL (sensitivity, 62%; specificity, 71%; AUC, 0.68), percentage of PSA change of a positive 289.50% (sensitivity, 48%; specificity, 82%; AUC, 0.64), PSA velocity of 0.033 ng/mL/wk (sensitivity, 57%; specificity, 80%; AUC, 0.70), and PSA DT of 7.91 mo (sensitivity, 71%; specificity, 62%; AUC, 0.67). Conclusion: Patients with recurrent PCa under observation after a negative 68Ga-PSMA-11 PET/CT scan with markedly elevated serum PSA levels and shorter PSA DT are more likely to have positive findings on repeat 68Ga-PSMA-11 PET/CT.




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Navigating the Future of Prostate Cancer Care: AI-Driven Imaging and Theranostics Through the Lens of RELAINCE




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EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit

EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit 12 December 2018 — 12:30PM TO 1:30PM Anonymous (not verified) 26 November 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

Turkey and the EU have been in a customs union since 1995. Both sides recognize that the current agreement is in need of modernization and have agreed to open negotiations to expand its scope to include services, public procurement, agriculture and other elements that would help bring it into the 21st century.

At the same time, the UK Parliament is debating whether to approve the agreement on the UK’s withdrawal from the EU. It includes a backstop which – if triggered – would keep the UK and the EU in a single customs territory which would limit the disruption of withdrawal but hamper Britain’s ability to pursue an independent trade policy. The political declaration proposes building on this customs arrangement as the basis for the future relationship.

In this context, the speaker will discuss the current EU-Turkey customs union arrangement and its shortcomings, examine the prospects for its modernization and share his insights on the lessons for the UK’s future trading relationship with the EU.

The event will launch the briefing paper ‘EU-Turkey Customs Union: Prospects for Modernization and Lessons for Brexit’.

Attendance at this event is by invitation only.




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Canucks Gameday Preview #14: Vancouver's Top Prospect Debuts Against The Flames

The Vancouver Canucks take on the Calgary Flames on Tuesday night.




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Ottawa Senators Send Forward Prospect Back Down To The Minors

Zack Ostapchuk returns to Belleville after posting one assist in six games with the big club.




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Maple Leafs Prospect Deserves A Solid Shot In The NHL After Emergency Call-Up

The Maple Leafs called up leading Marlies scorer Alex Steeves but aren't expected to play him. He deserves a good look while other bottom-six players struggle, says Adam Proteau.




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Praying for a woman in prostitution

An OM team in Hong Kong listens to the story of a woman in prostitution and offer her comfort and prayers.




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News24 Business | Nobel economics prize goes to researchers of prosperity

US-based academics Daron Acemoglu, Simon Johnson and James Robinson won the 2024 Nobel economics prize "for studies of how institutions are formed and affect prosperity", the Royal Swedish Academy of Sciences said on Monday.




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Penn State Berks offers Saturday tour for prospective students, Nov. 9

Prospective students and their families are invited to tour Penn State Berks at 10 a.m. Saturday, Nov. 9, with Lion Ambassador student tour guides.




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Prospective students invited to Penn State Day at Brandywine campus on Oct. 26

Prospective students and their families are invited to attend a visitation program at Penn State Brandywine at 9:30 a.m. on Saturday, Oct. 26, in the Commons/Athletic Center gymnasium. The event is part of the University’s "Penn State Day."




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DOJ releases February violent crime prosecution recap

Attorney General Kathy Jennings announced Friday that the Department of Justice charged 130 gun offenders and secured more than 245 total years in prison sentences on 18 gun convictions in the month of February.  Since 2019, the DOJ has an 83% conviction rate in Superior Court gun cases. “My first priority is combatting violent crime—particularly gun […]



  • Department of Justice
  • Department of Justice Press Releases
  • News

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DOJ Releases March Violent Crime Prosecution Recap 

Attorney General Kathy Jennings announced Friday that the Department of Justice charged 102 gun offenders and secured 279.5 total years in prison sentences on 67 gun convictions in the month of March. “My first priority is combatting violent crime—particularly gun crimes,” said AG Jennings.  “Gun violence is a both a national crisis and a local one. In Delaware, […]



  • Department of Justice
  • Department of Justice Press Releases
  • News

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Prosecutors Secure 40 Convictions In NorthPak Gang Trial

The Department of Justice has secured 40 convictions, including multiple murder and attempted murder charges, against two members of the violent Wilmington-area gang NorthPak, Attorney General Kathy Jennings announced Wednesday. “Thanks to an outstanding trial team and tireless investigators, led by the Wilmington Police Department, justice was delivered today,” said Attorney General Jennings. “These verdicts, […]



  • Department of Justice
  • Department of Justice Press Releases
  • News

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Prosecutors Secure Conviction in 2021 Murder Case

A King of Prussia man has been convicted for the 2021 stalking and murder of Nicole Crawford. On March 16, Justin Chaffier, 36, was found guilty of Murder 1st  Degree in addition to a felony Stalking charge. The conviction followed an investigation in which it was confirmed through multiple Ring camera videos, phone records, and DNA testing that […]



  • Department of Justice
  • Department of Justice Press Releases
  • News

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Prosecutors Secure Convictions Against Serial Child Abusers

The Delaware Department of Justice has secured multiple felony convictions against a Kent County couple charged with the serial abuse and torture of their children, Attorney General Kathy Jennings announced Wednesday. “These are the cases that keep us up at night,” said Attorney General Jennings. “The pain that these children endured — and that it […]



  • Department of Justice
  • Department of Justice Press Releases
  • News

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Prosecutors secure conviction against Jordan Ellerbe’s murderer

A Wilmington man has been convicted of the January 2015 murder of 16-year-old Jordan Ellerbe. Oliver “Butter” Henry, 25, has pleaded guilty to Murder 2nd Degree and faces a minimum 15 years in prison.  Ellerbe’s murder ignited a rapidly accelerating feud between two rival gangs, Shoot to Kill and Only My Brothers. In the months and […]



  • Department of Justice Press Releases

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ICYMI: Governor Carney op-ed in The News Journal: “Innovation is Delaware’s path to jobs and prosperity”

WILMINGTON, Del. – Governor John Carney on Sunday published an op-ed in The News Journal titled, “Innovation is Delaware’s path to jobs and prosperity.” In the op-ed, Governor Carney outlines what his administration is doing differently to transition Delaware’s economy, to keep the state competitive, and to make sure Delaware is positioned to create good-paying […]




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Cold case cracked as prosecutors secure murder plea

A Wilmington man has been convicted in a nearly four-year-long cold case. On May 15, Dashawn Daley, 29, of Wilmington pleaded guilty to Murder 2nd Degree, and Possession of a Firearm During the Commission of a Felony. This conviction follows an investigation into the fatal 2019 shooting of then 29-year-old Hakeem Smalls. “I am grateful […]



  • Department of Justice
  • Department of Justice Press Releases
  • News

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Fresh prospects for Australian mining equipment, technology and services (METS) in Saudi Arabia

Saudi Arabia’s Vision 2030 identifies mining as a key component of the Kingdom’s industry strategy. This will open major opportunities for Australian companies in the mining, equipment, technology and services (METS) sector.




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Mohbad’s ally Spending raises the alarm over alleged prosecution plot

Ayobami Sodiq, aka Spending, who is an ally of the late music star, Ilerioluwa Aloba aka Mohbad, has raised the alarm over alleged plots to prosecute him over the singer’s death. Spending’s legal counsel, Bonajo Badejo & Co, represented by Stephen Ehinmowo, in a statement on Tuesday and obtained by PUNCH Metro, raised concerns regarding


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The Start of Peace and Prosperity on the Korean Peninsula

The Start of Peace and Prosperity on the Korean Peninsula The Start of Peace and Prosperity on the Korean Peninsula
ferrard Wed, 08/29/2018 - 15:55

East-West Wire

Tagline
News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

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East-West Wire

Tagline
News, Commentary, and Analysis
East-West Wire

The East-West Wire is a news, commentary, and analysis service provided by the East-West Center in Honolulu. Any part or all of the Wire content may be used by media with attribution to the East-West Center or the person quoted. To receive East-West Center Wire media releases via email, subscribe here.

For links to all East-West Center media programs, fellowships and services, see www.eastwestcenter.org/journalists.

Explore




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ICC confirms probe into alleged misconduct by war crimes prosecutor

AMSTERDAM — The International Criminal Court's governing body will launch an external probe into its chief prosecutor Karim Khan over alleged sexual misconduct, it said in a statement on Monday, confirming a previous report by Reuters. "An external investigation is ... being pursued in order to ensure a fully independent, impartial and fair process," the statement said, also calling upon all parties to cooperate fully. Khan said in a statement that he would stay on in his key function of overseeing investigations into alleged war crimes, including in the Israel-Gaza conflict, while any issues relevant to the investigation would be handled by deputy prosecutors. Khan has previously denied allegations of misconduct that were reported to the court's governing body last month. At that time, he asked the court's own internal oversight body to investigate them. ICC judges are reviewing Khan's May request for arrest warrants against Israeli Prime Minister Netanyahu, his defense chief and Hamas leaders. Khan said the misconduct allegations aligned with a misinformation campaign against his office. The ICC is a permanent court that can prosecute individuals for war crimes, crimes against humanity, genocide and the crime of aggression in member states or by their nationals.




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Argentine prosecutors charge 3 linked to death of former One Direction star Liam Payne

BUENOS AIRES — Three people have been charged in connection with the death of Liam Payne, a former member of musical group One Direction who died after falling from the balcony of his hotel room in Buenos Aires last month, Argentine prosecutors said Thursday. Prosecutor Andrés Madrea charged the three suspects, whose identities were not revealed, with the crimes of "abandonment of a person followed by death" and "supplying and facilitating the use of narcotics," the prosecutor's office said. Madrea also requested their arrest to judge Laura Bruniard, who ruled the three cannot leave the country. Payne fell from his room's balcony on the third floor of his hotel in the upscale neighborhood of Palermo, in the Argentine capital. His autopsy said he died from multiple injuries and external bleeding. Prosecutors also said that Payne's toxicological exams showed that his body had "traces of alcohol, cocaine and a prescribed antidepressant" in the moments before his death. Investigators said hours after Payne's death that he was by himself when he fell. But the prosecutors' office said Thursday that one of the people charged was often with the singer during his time in Buenos Aires. The second is a hotel staffer who allegedly gave Payne cocaine during his stay between October 13 and 16. And the third is a drug dealer. The charges in Payne's case bear some resemblance to the U.S. cases stemming from the death of Friends star Matthew Perry a year ago. The actor's personal assistant and a longtime friend are among those charged with helping supply him with ketamine in the final months of his life, leading up to his overdose on the anesthetic. Three young men were similarly charged in the opioid-overdose death of rapper Mac Miller in 2018. Local authorities gathered, among other pieces of evidence, Payne's cellphone records, material for forensics and testimonies. They are yet to unlock the singer's personal computer – which is damaged – and other devices that were seized. Payne's autopsy showed his injuries were neither caused by self-harm nor by physical intervention of others. The document also said that he did not have the reflex of protecting himself in the fall, which suggests he might have been unconscious. Prosecutors in Argentina also ruled out the chances of Payne dying by suicide. One Direction was among the most successful boy bands of recent times. It announced an indefinite hiatus in 2016 and Payne — like his former bandmates Zayn Malik, Harry Styles, Niall Horan, and Louis Tomlinson — pursued a solo career. The singer had posted on his Snapchat account that he traveled to Argentina to attend Horan's concert in Buenos Aires on October 2. He shared videos of himself dancing with his girlfriend, American influencer Kate Cassidy, and singing along in the stands. Cassidy had left Argentina after the show, but Payne stayed behind. 




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The Holy Spirit: God’s Prosecutor




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“Escalation Dominance” . . . and the Prospect of More Than 1,000 Holocausts

Everything is at stake. Everything is at stake with nuclear weapons. While working as a nuclear war planner for the Kennedy administration, Daniel Ellsberg was shown a document calculating that a U.S. nuclear attack on communist countries would result in 600 million dead. As he put it later: “A hundred Holocausts.” That was in 1961. […]




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Prostitution an ‘Egregious Violation of Human Rights’—UN Special Rapporteur

Reem Alsalem, the UN Special Rapporteur on Violence Against Women and Girls, calls prostitution a “system of violence” that does not benefit society at all, especially the women and girls forced into this system. Alsalem spoke at the Roosevelt House Public Policy Institute in New York on Wednesday, October 2, to discuss her special report […]




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Prospects of India–Bangladesh Economic Cooperation: Implications for South Asian Regional Cooperation

Bangladesh and India should pursue bilateral economic cooperation to enhance South Asian regional cooperation.



  • Publications/Papers and Briefs

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We are finally improving prostate cancer diagnoses - here's how

Cases of prostate cancer are surging alarmingly around the world. Thankfully, we are developing more accurate tests that can catch the condition early




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The Biology of Kindness review: Living well and prospering

Can cultivating positive behaviours and tweaking our lifestyles lead to healthier, happier lives – even longer lives? Discover the daily choices that may make the difference in a fascinating new book




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Initial Savings May Hide True Cost of Prostate Cancer Care

Title: Initial Savings May Hide True Cost of Prostate Cancer Care
Category: Health News
Created: 8/23/2010 12:10:00 PM
Last Editorial Review: 8/24/2010 12:00:00 AM




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Breast Cancer Drug Might Help Men on Prostate Cancer Therapy

Title: Breast Cancer Drug Might Help Men on Prostate Cancer Therapy
Category: Health News
Created: 8/28/2012 10:05:00 AM
Last Editorial Review: 8/28/2012 12:00:00 AM




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Daily Aspirin May Help Fight Prostate Cancer, But Not Breast Cancer

Title: Daily Aspirin May Help Fight Prostate Cancer, But Not Breast Cancer
Category: Health News
Created: 8/27/2012 6:05:00 PM
Last Editorial Review: 8/28/2012 12:00:00 AM




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Race May Affect Quality of Prostate Cancer Surgical Care

Title: Race May Affect Quality of Prostate Cancer Surgical Care
Category: Health News
Created: 8/28/2012 6:05:00 PM
Last Editorial Review: 8/29/2012 12:00:00 AM




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Could Heavy Coffee Drinking Help Men Battle Prostate Cancer?

Title: Could Heavy Coffee Drinking Help Men Battle Prostate Cancer?
Category: Health News
Created: 8/26/2013 7:36:00 PM
Last Editorial Review: 8/27/2013 12:00:00 AM




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Common Treatment for Early Prostate Cancer May Carry Heart Risk

Title: Common Treatment for Early Prostate Cancer May Carry Heart Risk
Category: Health News
Created: 8/25/2017 12:00:00 AM
Last Editorial Review: 8/28/2017 12:00:00 AM




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Is Teen Drinking Tied to Aggressive Prostate Cancer Later in Life?

Title: Is Teen Drinking Tied to Aggressive Prostate Cancer Later in Life?
Category: Health News
Created: 8/29/2018 12:00:00 AM
Last Editorial Review: 8/29/2018 12:00:00 AM




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Enlarged Prostate Doesn't Raise a Man's Odds for Cancer: Study

Title: Enlarged Prostate Doesn't Raise a Man's Odds for Cancer: Study
Category: Health News
Created: 8/25/2021 12:00:00 AM
Last Editorial Review: 8/25/2021 12:00:00 AM




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Prostate Problems

Title: Prostate Problems
Category: Diseases and Conditions
Created: 10/16/2002 12:00:00 AM
Last Editorial Review: 7/21/2022 12:00:00 AM




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Prostatitis (Inflammation of the Prostate Gland)

Title: Prostatitis (Inflammation of the Prostate Gland)
Category: Diseases and Conditions
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 7/29/2022 12:00:00 AM




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Patient-managed interventions for adults with bronchiectasis: evidence, challenges and prospects

Bronchiectasis is a chronic lung condition which is characterised by recurrent chest infections, chronic sputum production and cough, and limited exercise tolerance. While bronchiectasis may be caused by various aetiologies, these features are shared by most patients with bronchiectasis regardless of the cause. This review consolidates the existing evidence on patient-managed interventions for adults with bronchiectasis, while also outlining areas for future research. Airway clearance techniques and hyperosmolar agents are key components of the bronchiectasis management and consistently recommended for clinical implementation. Questions around their prescription, such as optimal sequence of delivery, are still to be answered. Pulmonary rehabilitation and exercise are also recommended for patients with bronchiectasis. Relatively strong evidence underpins this recommendation during a clinically stable stage of the disease, although the role of pulmonary rehabilitation following an exacerbation is still unclear. Additionally, self-management programmes feature prominently in bronchiectasis treatment, yet the lack of consensus regarding their definition and outcomes presents hurdles to establishing a cohesive evidence base. Moreover, cough, a cardinal symptom of bronchiectasis, warrants closer examination. Although managing cough in bronchiectasis may initially appear risky, further research is necessary to ascertain whether strategies employed in other respiratory conditions can be safely and effectively adapted to bronchiectasis, particularly through identifying patient responder populations and criteria where cough may not enhance airway clearance efficacy and its control is needed. Overall, there is a growing recognition of the importance of patient-managed interventions in the bronchiectasis management. Efforts to improve research methodologies and increase research funding are needed to further advance our understanding of these interventions, and their role in optimising patient care and outcomes.




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Longitudinal validation of King's Sarcoidosis Questionnaire in a prospective cohort with mild sarcoidosis

Background

Quality of life is impaired in patients with sarcoidosis. The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health-related quality of life in patients with sarcoidosis, comprising subdomains of General Health Status (GHS), Lung, Medication, Skin and Eyes. The aim of this study was to enhance the validation of the KSQ, incorporating longitudinal validation and known-groups validity in a cohort with mild sarcoidosis.

Methods

The KSQ was linguistically validated according to guidelines. Patients with sarcoidosis completed KSQ and other questionnaires at baseline, after 2 weeks and at 12 months. Forced vital capacity (FVC) was measured. Concurrent validity, reliability and responsiveness were assessed.

Results

In patients (n=150), the KSQ had moderate to strong correlations with the Short Form-12 (Mental Component Summary), the King's Brief Interstitial Lung Disease questionnaire and the Fatigue Assessment Scale (r=0.30–0.70) and weak correlations with the Short Form-12 (Physical Component Summary) and FVC (r=0.01–0.29). The KSQ GHS and Lung domains were able to discriminate between groups of patients stratified according to fatigue, treatment and FVC. The KSQ had high internal consistency (Cronbach's α=0.73–0.90) and repeatability (interclass correlation coefficients 0.72–0.81). Correlations to comparable questionnaires at baseline were moderate or strong for the GHS, Lung and GHS–Lung subdomains and weak or moderate for FVC. The KSQ was responsive to changes over time.

Conclusion

This study strengthened the validation of the KSQ by introducing known-groups validity and assessments of responsiveness over 12 months in patients with mild sarcoidosis.




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Characterization and Prediction of Organic Anion Transporting Polypeptide 1B Activity in Prostate Cancer Patients on Abiraterone Acetate Using Endogenous Biomarker Coproporphyrin I [Articles]

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are important hepatic transporters. We previously identified OATP1B3 being critically implicated in the disposition of abiraterone. We aimed to further investigate the effects of abiraterone on the activities of OATP1B1 and OATP1B3 utilizing a validated endogenous biomarker coproporphyrin I (CP-I). We used OATP1B-transfected cells to characterize the inhibitory potential of abiraterone against OATP1B-mediated uptake of CP-I. Inhibition constant (Ki) was incorporated into our physiologically based pharmacokinetic (PBPK) modeling to simulate the systemic exposures of CP-I among cancer populations receiving either our model-informed 500 mg or clinically approved 1000 mg abiraterone acetate (AA) dosage. Simulated data were compared with clinical CP-I concentrations determined among our nine metastatic prostate cancer patients receiving 500 mg AA treatment. Abiraterone inhibited OATP1B3-mediated, but not OATP1B1-mediated, uptake of CP-I in vitro, with an estimated Ki of 3.93 μM. Baseline CP-I concentrations were simulated to be 0.81 ± 0.26 ng/ml and determined to be 0.72 ± 0.16 ng/ml among metastatic prostate cancer patients, both of which were higher than those observed for healthy subjects. PBPK simulations revealed an absence of OATP1B3-mediated interaction between abiraterone and CP-I. Our clinical observations confirmed that CP-I concentrations remained comparable to baseline levels up to 12 weeks post 500 mg AA treatment. Using CP-I as an endogenous biomarker, we identified the inhibition of abiraterone on OATP1B3 but not OATP1B1 in vitro, which was predicted and observed to be clinically insignificant. We concluded that the interaction risk between AA and substrates of OATP1Bs is low.

SIGNIFICANCE STATEMENT

The authors used the endogenous biomarker coproporphyrin I (CP-I) and identified abiraterone as a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B3 in vitro. Subsequent physiologically based pharmacokinetic (PBPK) simulations and clinical observations suggested an absence of OATP1B-mediated interaction between abiraterone and CP-I among prostate cancer patients. This multipronged study concluded that the interaction risk between abiraterone acetate and substrates of OATP1Bs is low, demonstrating the application of PBPK-CP-I modeling in predicting OATP1B-mediated interaction implicating abiraterone.




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CYP8B1 Catalyzes 12alpha-Hydroxylation of C27 Bile Acid: In Vitro Conversion of Dihydroxycoprostanic Acid into Trihydroxycoprostanic Acid [Articles]

Sterol 12α-hydroxylase (CYP8B1) is the unique P450 enzyme with sterol 12-oxidation activity, playing an exclusive role in 12α-hydroxylating intermediates along the bile acid (BA) synthesis pathway. Despite the long history of BA metabolism studies, it is unclear whether CYP8B1 catalyzes 12α-hydroxylation of C27 BAs, the key intermediates shuttling between mitochondria and peroxisomes. This work provides robust in vitro evidence that both microsomal and recombinant CYP8B1 enzymes catalyze the 12α-hydroxylation of dihydroxycoprostanic acid (DHCA) into trihydroxycoprostanic acid (THCA). On the one hand, DHCA 12α-hydroxylation reactivity is conservatively detected in liver microsomes of both human and preclinical animals. The reactivity of human tissue fractions conforms well with the selectivity of CYP8B1 mRNA expression, while the contribution of P450 enzymes other than CYP8B1 is excluded by reaction phenotyping in commercial recombinant enzymes. On the other hand, we prepared functional recombinant human CYP8B1 proteins according to a recently published protocol. Titration of the purified CYP8B1 proteins with either C4 (7α-hydroxy-4-cholesten-3-one) or DHCA yields expected blue shifts of the heme Soret peak (type I binding). The recombinant CYP8B1 proteins efficiently catalyze 12α-hydroxylation of both DHCA and C4, with substrate concentration occupying half of the binding sites of 3.0 and 1.9 μM and kcat of 3.2 and 2.6 minutes–1, respectively. In summary, the confirmed role of CYP8B1 in 12α-hydroxylation of C27 BAs has furnished the forgotten passageway in the BA synthesis pathway. The present finding might have opened a new window to consider the biology of CYP8B1 in glucolipid metabolism and to evaluate CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases.

SIGNIFICANCE STATEMENT

The academic community has spent approximately 90 years interpreting the synthesis of bile acids. However, the 12α-hydroxylation of intermediates catalyzed by CYP8B1 is not completely mapped on the classic pathway, particularly for the C27 bile acids, the pivotal intermediates shuttling between mitochondria and peroxisomes. This work discloses the forgotten 12α-hydroxylation pathway from dihydroxycoprostanic acid into trihydroxycoprostanic acid. The present finding may facilitate evaluating CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases.




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Freehand SPECT Combined with 3-Dimensional Light Detection and Ranging as Alternative Means of Specimen Scanning During Prostate Cancer Surgery




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Preclinical Investigation of [212Pb]Pb-DOTAM-GRPR1 for Peptide Receptor Radionuclide Therapy in a Prostate Tumor Model

The role of gastrin-releasing peptide receptor (GRPR) in various diseases, including cancer, has been extensively studied and has emerged as a promising therapeutic target. In this study, we successfully achieved the use of [212Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, 212Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Methods: Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor–bearing mice after intravenous administration of [212Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Results: Preclinical studies have shown tumor targeting of up to 5 percent injected dose per gram over 24 h, and optimization of the drug formulation and quantity has led to minimized oxidation and off-target binding, respectively. Particularly, an increase in peptide amount from 28 to 280 ng was shown to reduce off-target uptake, especially at the level of the pancreas, by about 30%. Furthermore, dosimetry studies confirmed the kidney as the dose-limiting organ, and toxicity studies revealed that a nontoxic dose of up to 1,665 kBq could be injected into mice. Efficacy studies indicated a median survival time of 9 wk in the control group, which received only a buffer solution, compared with 19 wk in the group that received 4 injections of 370 kBq at 3-wk intervals. Conclusion: Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [212Pb]Pb-DOTAM-GRPR1, thus warranting further exploration in clinical trials.




pros

Efficacy and Toxicity of [177Lu]Lu-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: Results from the U.S. Expanded-Access Program and Comparisons with Phase 3 VISION Data

The phase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]–positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor–signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [177Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.




pros

Association of Free-to-Total PSA Ratio and 18F-DCFPyL Prostate-Specific Membrane Antigen PET/CT Findings in Patients with Biochemical Recurrence After Radical Prostatectomy: A Prospective Single-Center Study

In Canada and across the globe, access to PSMA PET/CT is limited and expensive. For patients with biochemical recurrence (BCR) after treatment for prostate cancer, novel strategies are needed to better stratify patients who may or may not benefit from a PSMA PET scan. The role of the free-to-total prostate-specific antigen (PSA) ratio (FPSAR) in posttreatment prostate cancer, specifically in the PSMA PET/CT era, remains unknown. Our aim in this study was to determine the association of FPSAR in patients referred for 18F-DCFPyL PSMA PET/CT in the BCR setting and assess the correlation between FPSAR and 18F-DCFPyL PSMA PET/CT positivity (local recurrence or distant metastases). Methods: This prospective study included 137 patients who were referred for 18F-DCFPyL PSMA PET/CT and had BCR with a total PSA of less than 1 ng/mL after radical prostatectomy (RP) (including adjuvant or salvage radiotherapy). Blood samples were collected on the day of 18F-DCFPyL PSMA PET/CT. FPSAR was categorized as less than 0.10 or as 0.10 or more. A positive 18F-DCFPyL PSMA PET/CT scan was defined by a PROMISE classification lesion score of 2 or 3, irrespective of the site of increased tracer uptake (e.g., prostate, pelvic nodes, bone, or viscera). Results: Overall, 137 blood samples of patients with BCR after RP were analyzed to calculate FPSAR. The median age at 18F-DCFPyL PSMA PET/CT was 68.6 y (interquartile range, 63.0–72.4 y), and the median PSA at 18F-DCFPyL PSMA PET/CT was 0.3 ng/mL (interquartile range, 0.3–0.6 ng/mL). Eighty-six patients (62.8%) had an FPSAR of less than 0.10, whereas 51 patients (37.2%) had an FPSAR of 0.10 or more. An FPSAR of 0.10 or more was identified as an independent predictor of a positive 18F-DCFPyL PSMA PET/CT scan, with an odds ratio of 6.99 (95% CI, 2.96–16.51; P < 0.001). Conclusion: An FPSAR of 0.10 or more after RP independently correlated with increased odds of a positive 18F-DCFPyL PSMA PET/CT scan among BCR post-RP patients. These findings may offer an inexpensive method by which to triage access to 18F-DCFPyL PSMA PET/CT in jurisdictions where availability is not replete.