bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b
Authors: Hosseini-Gerami Layla , Ficulle Elena , Humphryes-Kirilov Neil , Airey David C. , Scherschel James , Kananathan Sarubini , Eastwood Brian J. , Bose Suchira , Collier David A. , Laing Emma , Evans David , Broughton Howard , Bender Andreas
Published: March 2023

Background

A key histopathological hallmark of Alzheimer’s disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes.

Methods

In this work, we employed bioinformatics analysis—including pathway enrichment and causal reasoning—of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure.

Results

Combining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled “Superpathway of cholesterol biosynthesis” and “Granulocyte adhesion and diapedesis”. With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins.

Conclusions

This study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.
Attenuation of Alzheimer’s brain pathology in 5XFAD mice by PTH1-34, a peptide of parathyroid hormone
Authors: Chen Li , Xiong Lei , Yao Lingling , Pan Jinxiu , Arzola Emily , Zhu Xiaojuan , Mei Lin , Xiong Wen-Cheng
Published: March 2023

Background

Alzheimer’s disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model.

Methods

5XFAD mice, an early onset β-amyloid (Aβ)-based AD mouse model, were treated with PTH1-34intermittently [once daily injection of hPTH1–34(50 μg/Kg), 5 days/week, starting at 2-month old (MO) for 2–3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aβ and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope.

Results

A reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34treatments, not only these bone deficits but also Aβ-associated brain pathologies, including Aβ and Aβ deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice.

Conclusions

These results suggest that PTH1-34may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34’s therapeutic potential for patients with not only osteoporosis but also AD.
Fowl adenovirus serotype 4 enters leghorn male hepatocellular cells via the clathrin-mediated endocytosis pathway
Authors: Wang Ting , Wang Lizhen , Li Wei , Hou Xiaolan , Chang Wenchi , Wen Bo , Han Shuizhong , Chen Yan , Qi Xuefeng , Wang Jingyu
Published: March 2023

Hepatitis-hydropericardium syndrome (HHS) induced by fowl adenovirus serotype-4 (FAdV-4) has caused large economic losses to the world poultry industry in recent years. HHS is characterized by pericardial effusion and hepatitis, manifesting as a swollen liver with focal necroses and petechial haemorrhage. However, the process of FAdV-4 entry into hepatic cells remains largely unknown. In this paper, we present a comprehensive study on the entry mechanism of FAdV-4 into leghorn male hepatocellular (LMH) cells. We first observed that FAdV-4 internalization was inhibited by chlorpromazine and clathrin heavy chain (CHC) knockdown, suggesting that FAdV-4 entry into LMH cells depended on clathrin. By using the inhibitor dynasore, we showed that dynamin was required for FAdV-4 entry. In addition, we found that FAdV-4 entry was dependent on membrane cholesterol, while neither the knockdown of caveolin nor the inhibition of a tyrosine kinase-based signalling cascade affected FAdV-4 infection. These results suggested that FAdV-4 entry required cholesterol but not caveolae. We also found that macropinocytosis played a role, and phosphatidylinositol 3-kinase (PI3K) was required for FAdV-4 internalization. However, inhibitors of endosomal acidification did not prevent FAdV-4 entry. Taken together, our findings demonstrate that FAdV-4 enters LMH cells through dynamin- and cholesterol-dependent clathrin-mediated endocytosis, accompanied by the involvement of macropinocytosis requiring PI3K. Our work potentially provides insight into the entry mechanisms of other avian adenoviruses.
The efficacy of high-flow nasal cannula (HFNC) versus non-invasive ventilation (NIV) in patients at high risk of extubation failure: a systematic review and meta-analysis
Authors: Wang Qiaoying , Peng Yanchun , Xu Shurong , Lin Lingyu , Chen Liangwan , Lin Yanjuan
Published: March 2023

Background

Studies suggest that high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) can prevent reintubation in critically ill patients with a low risk of extubation failure. However, the safety and effectiveness in patients at high risk of extubation failure are still debated. Therefore, we conducted a systematic review and meta-analysis to compare the efficacies of HFNC and NIV in high-risk patients.

Methods

We searched eight databases (MEDLINE, Cochrane Library, EMBASE, CINAHL Complete, Web of Science, China National Knowledge Infrastructure, Wan-Fang Database, and Chinese Biological Medical Database) with reintubation as a primary outcome measure. The secondary outcomes included mortality, intensive care unit (ICU) length of stay (LOS), incidence of adverse events, and respiratory function indices. Statistical data analysis was performed using RevMan software.

Results

Thirteen randomized clinical trials (RCTs) with 1457 patients were included. The HFNC and NIV groups showed no differences in reintubation (RR 1.10, 95% CI 0.87–1.40, I2 = 0%, P = 0.42), mortality (RR 1.09, 95% CI 0.82–1.46, I2 = 0%, P = 0.54), and respiratory function indices (partial pressure of carbon dioxide [PaCO2]: MD − 1.31, 95% CI − 2.76–0.13, I2 = 81%, P = 0.07; oxygenation index [P/F]: MD − 2.18, 95% CI − 8.49–4.13, I2 = 57%, P = 0.50; respiratory rate [Rr]: MD − 0.50, 95% CI − 1.88–0.88, I2 = 80%, P = 0.47). However, HFNC reduced adverse events (abdominal distension: RR 0.09, 95% CI 0.04–0.24, I2 = 0%, P < 0.01; aspiration: RR 0.30, 95% CI 0.09–1.07, I2 = 0%, P = 0.06; facial injury: RR 0.27, 95% CI 0.09–0.88, I2 = 0%, P = 0.03; delirium: RR 0.30, 95%CI 0.07–1.39, I2 = 0%, P = 0.12; pulmonary complications: RR 0.67, 95% CI 0.46–0.99, I2 = 0%, P = 0.05; intolerance: RR 0.22, 95% CI 0.08–0.57, I2 = 0%, P < 0.01) and may have shortened LOS (MD − 1.03, 95% CI − 1.86–− 0.20, I2 = 93%, P = 0.02). Subgroup analysis by language, extubation method, NIV parameter settings, and HFNC flow rate revealed higher heterogeneity in LOS, PaCO2, and Rr.

Conclusions

In adult patients at a high risk of extubation failure, HFNC reduced the incidence of adverse events but did not affect reintubation and mortality. Consequently, whether or not HFNC can reduce LOS and improve respiratory function remains inconclusive.
New insights into the impact of microbiome on horizontal and vertical transmission of a tick-borne pathogen
Authors: Du Li-Feng , Zhang Ming-Zhu , Yuan Ting-Ting , Ni Xue-Bing , Wei Wei , Cui Xiao-Ming , Wang Ning , Xiong Tao , Zhang Jie , Pan Yu-Sheng , Zhu Dai-Yun , Li Liang-Jing , Xia Luo-Yuan , Wang Tian-Hong , Wei Ran , Liu Hong-Bo , Sun Yi , Zhao Lin , Lam Tommy Tsan-Yuk , Cao Wu-Chun , Jia Na
Published: March 2023

Background

The impact of host skin microbiome on horizontal transmission of tick-borne pathogens , and of pathogen associated transstadial and transovarial changes in tick microbiome are largely unknown, but are important to control increasingly emerging tick-borne diseases worldwide.

Methods

Focusing on a rickettsiosis pathogen, Rickettsia raoultii, we used R. raoultii-positive and R. raoultii-negative Dermacentor spp. tick colonies to study the involvement of skin microbiota in cutaneous infection with rickettsiae in laboratory mice, and the function of the tick microbiome on maintenance of rickettsiae through all tick developmental stages (eggs, larvae, nymphs, adults) over two generations.

Results

We observed changes in the skin bacteria community, such as Chlamydia, not only associated with rickettsial colonization but also with tick feeding on skin. The diversity of skin microbiome differed between paired tick-bitten and un-bitten sites. For vertical transmission, significant differences in the tick microbiota between pathogenic rickettsia-positive and -negative tick chorts was observed across all developmental stages at least over two generations, which appeared to be a common pattern not only for R. raoultii but also for another pathogenic species, Candidatus Rickettsia tarasevichiae. More importantly, bacterial differences were complemented by functional shifts primed for genetic information processing during blood feeding. Specifically, the differences in tick microbiome gene repertoire between pathogenic Rickettsia-positive and -negative progenies were enriched in pathways associated with metabolism and hormone signals during vertical transmission.

Conclusions

We demonstrate that host skin microbiome might be a new factor determining the transmission of rickettsial pathogens through ticks. While pathogenic rickettsiae infect vertebrate hosts during blood-feeding by the tick, they may also manipulate the maturation of the tick through changing the functional potential of its microbiota over the tick’s life stages. The findings here might spur the development of new-generation control methods for ticks and tick-borne pathogens.
The psychological impact of the COVID-19 outbreak among the fever patients in the lockdown zone
Authors: Chen Yuewei , Ma Qian , Xie Xiaoshuai , Cao Kekui , Hou Zhencai , Zhang Peiyi
Published: March 2023

Background

COVID-19 pandemic is still ongoing, which not only impact physical health but psychological health. This research aims to analyze the psychological impact of residents with a fever (> 37 °C) during the COVID-19 outbreak in one community.

Methods

There were 105 participants surveyed online from 7th March to 21st March 2022. Collected the data included the socio-demographics, health status, COVID-19 knowledge and concerns and the Impact of Events Scale-Revised (IES-R) ratings.

Results

Among those participants, the IES-R mean score was 24.11 (SD = 6.12), and 30.48% of respondents reported a moderate to the severe psychological impact. Female gender; youth age; single status; other specific symptoms; concerns about family members, and discrimination were significantly associated with the greater psychological impact of the COVID-19 event (p < 0.05).

Conclusions

In the lockdown zone, about one-third of the residents have an obvious psychological impact after fever. The factors identified can be used to make effective psychological support strategies in the early stages of the COVID-19 outbreak.
Prevalence and associated factors of incident and persistent loneliness among middle-aged and older adults in Thailand
Authors: Pengpid Supa , Peltzer Karl
Published: March 2023

Background

The aim of the study was to assess the prevalence and associated factors of incident and persistent loneliness in a prospective cohort study among middle-aged and older adults (≥ 45 years) in Thailand.

Methods

Longitudinal data from the Health, Aging, and Retirement in Thailand (HART) study in 2015 and 2017 were analysed. Loneliness was assessed with one item from the Center for Epidemiological Studies Depression scale. Logistic regression was used to calculate predictors of incident and persistent loneliness.

Results

In total, at baseline 21.7% had loneliness, 633 of 3696 participants without loneliness in 2015 had incident loneliness in 2017 (22.2%), and 239 of 790 adults had persistent loneliness (in both 2015 and 2017) (30.3%). In adjusted logistic regression analysis, low income (aOR: 1.27, 95% CI: 1.03 to 1.57), poor self-rated physical health status (aOR: 1.64, 95% CI: 1.27 to 2.12), hypertension (aOR: 1.34, 95% CI: 1.09 to 1.65), depressive symptoms (aOR: 1.97, 95% CI: 1.11 to 3.49), and having three or chronic conditions (aOR: 1.76, 95% CI: 1.19 to 2.60) were positively associated and a higher education (aOR: 0.74, 95% CI: 0.55 to 0.98) and living in the southern region of Thailand (aOR: 0.43, 95% CI: 0.30 to 0.61) were inversely associated with incident loneliness. Poor self-rated physical health status (aOR: 1.91, 95% CI: 1.26 to 2.88), and having three or more chronic diseases (aOR: 1.78, 95% CI: 1.07 to 2.98), were positively associated, and living in the southern region (aOR: 0.40, 95% CI: 0.25 to 0.65) was inversely associated with persistent loneliness.

Conclusion

More than one in five ageing adults had incident loneliness in 2 years of follow-up. The prevalence of incident and/or persistent loneliness was higher in people with a lower socioeconomic status, residing in the central region, poor self-rated physical health status, depressive symptoms, hypertension, and a higher number of chronic diseases.
Computer‐assisted analysis of functional internal rotation after reverse total shoulder arthroplasty: implications for component choice and orientation
Authors: Hochreiter Bettina , Meisterhans Michel , Zindel Christoph , Calek Anna‐Katharina , Gerber Christian
Published: March 2023

Purpose

Functional internal rotation (IR) is a combination of extension and IR. It is clinically often limited after reverse total shoulder arthroplasty (RTSA) either due to loss of extension or IR in extension. It was the purpose of this study to determine the ideal in‐vitro combination of glenoid and humeral components to achieve impingement‐free functional IR.

Methods

RTSA components were virtually implanted into a normal scapula (previously established with a statistical shape model) and into a corresponding humerus using a computer planning program (CASPA). Baseline glenoid configuration consisted of a 28 mm baseplate placed flush with the posteroinferior glenoid rim, a baseplate inclination angle of 96° (relative to the supraspinatus fossa) and a 36 mm standard glenosphere. Baseline humeral configuration consisted of a 12 mm humeral stem, a metaphysis with a neck shaft angle (NSA) of 155° (+ 6 mm medial offset), anatomic torsion of ‐20° and a symmetric PE inlay (36mmx0mm). Additional configurations with different humeral torsion (‐20°, + 10°), NSA (135°, 145°, 155°), baseplate position, diameter, lateralization and inclination were tested. Glenohumeral extension of 5, 10, 20, and 40° was performed first, followed by IR of 20, 40, and 60° with the arm in extension of 40°—the value previously identified as necessary for satisfactory clinical functional IR. The different component combinations were taken through simulated ROM and the impingement volume (mm3) was recorded. Furthermore, the occurrence of impingement was read out in 5° motion increments.

Results

In all cases where impingement occurred, it occurred between the PE inlay and the posterior glenoid rim. Only in 11 of 36 combinations full functional IR was possible without impingement. Anterosuperior baseplate positioning showed the highest impingement volume with every combination of NSA and torsion. A posteroinferiorly positioned 26 mm baseplate resulting in an additional 2 mm of inferior overhang as well as 6 mm baseplate lateralization offered the best impingement‐free functional IR (5/6 combinations without impingement). Low impingement potential resulted from a combination of NSA 135° and + 10° torsion (4/6 combinations without impingement), followed by NSA 135° and ‐20° torsion (3/6 combinations without impingement) regardless of glenoid setup.

Conclusion

The largest impingement‐free functional IRs resulted from combining a posteroinferior baseplate position, a greater inferior glenosphere overhang, 90° of baseplate inclination angle, 6 mm glenosphere lateralization with respect to baseline setup, a lower NSA and antetorsion of the humeral component. Surgeons can employ and combine these implant configurations to achieve and improve functional IR when planning and performing RTSA.

Level of evidence

Basic Science Study, Biomechanics.
Prevalence of Sjögren's syndrome according to 2016 ACR-EULAR classification criteria in patients with systemic lupus erythematosus
Authors: Gianordoli Ana Paula Espíndula , Laguardia Rafaella Vila Real Barbosa , Santos Maria Carmen F. S. , Jorge Fabiano Cade , da Silva Salomão Amanda , Caser Larissa Carvalho , Moulaz Isac Ribeiro , Serrano Érica Vieira , Miyamoto Samira Tatiyama , Machado Ketty Lysie Libardi Lira , Valim Valéria
Published: March 2023

Background

Diagnosis of SS is a complex task, as no symptom or test is unique to this syndrome. The American-European Consensus Group (AECG 2002) and the American-European classification criteria of 2016 (ACR/EULAR 2016) emerged through a search for consensus. This study aims to assess the prevalence of Sjögren’s Syndrome (SS) in patients with Systemic Lupus Erythematosus (SLE), according to AECG 2002 and ACR-EULAR 2016 classifications, as well as clinical and histopathological features in this overlap. To date, there is no study that has evaluated SS in SLE, using the two current criteria.

Methods

This cross-sectional study evaluated 237 SLE patients at the outpatient rheumatology clinic between 2016 and 2018. Patients were submitted to a dryness questionnaire, whole unstimulated salivary flow (WUSF), “Ocular Staining Score” (OSS), Schirmer’s test I (ST-I), and labial salivary gland biopsy (LSGB).

Results

After verifying inclusion and exclusion criteria, a total of 117 patients were evaluated, with predominance of females (94%) and mixed ethnicity (49.6%). The prevalence of SS was 23% according to AECG 2002 and 35% to ACR-EULAR 2016. Kappa agreement between AECG 2002 and ACR-EULAR 2016 were 0.7 (p < 0.0001). After logistic regression, predictors for SS were: anti/Ro (OR = 17.86, p < 0.05), focal lymphocytic sialadenitis (OR = 3.69, p < 0.05), OSS ≥ 5 (OR = 7.50, p < 0.05), ST I positive (OR = 2.67, p < 0.05), and WUSF ≤ 0.1 mL/min (OR = 4.13, p < 0.05).

Conclusion

The prevalence of SS in SLE was 23% (AECG 2002) and 35% (ACR-EULAR 2016). The presence of glandular dysfunction, focal lymphocytic sialadenitis, and anti/Ro were predictors of SS in SLE. The greatest advantage of the new ACR-EULAR 2016 criteria is to enable an early diagnosis and identify the overlapping of these two diseases. ACR-EULAR 2016 criteria is not yet validated for secondary SS and this study is a pioneer in investigating prevalence based on the new criteria.
Patient (pt) perspective on fatigue and its management for advanced prostate cancer (PC) treated with androgen receptor inhibitors (ARIs).
Authors: Freedland Stephen J. , Chakoian Marty , Wells Edward , El-Chaar Nader N. , Colon Alexandra , Elsounda Dina , Hong Agnes
Published: March 2023

100

Background: Fatigue is a common, multifaceted disease- and treatment (tx)-related symptom experienced by pts with advanced PC (aPC). Although fatigue of variable severity has been reported across clinical trials in pts with metastatic hormone-sensitive PC (also referred to as metastatic castration-sensitive PC [mCSPC]) and non-metastatic castration-resistant PC (nmCRPC) treated with ARIs, there is limited real-world insight from the pt’s perspective or guidance on the management of this symptom. This study assessed pts’ experience with fatigue and self-reported management strategies. Methods: In this cross-sectional non-interventional qualitative research study, pts receiving ARIs were interviewed about their fatigue experience and management strategies. All pts were ≥18 years, diagnosed with mCSPC or nmCRPC, currently on ARI tx (enzalutamide, apalutamide or darolutamide) that began ≤24 months (mo) prior to interview and experienced fatigue. Descriptive data extracted were organized into general concepts and presented as number and frequency of reports. Results: Among 143 screened pts, 11 completed the interview (mCSPC, 7; nmCRPC, 4). Most were White, mean age was 63 years and median time since ARI initiation was 12 mo. Pts described their fatigue experience as a physical, emotional or mental feeling that impacted activities of daily living. Pts attributed their fatigue to more than one cause including, but not limited to: a side effect of ARI tx, emotional burden of disease, or physical exertion. Most pts did not feel adequately prepared and indicated they would have liked to receive additional education or support to manage tx-related fatigue. As a result, most pts followed self-initiated management strategies such as healthy diet, rigorous exercise and increased rest, which were reported to be effective for some pts. Conclusions: Pts with aPC emphasized the lack of adequate knowledge and health care provider (HCP) recommendations for managing fatigue. Hence, there is a need to develop recommendations for fatigue management and resources to support HCPs’ counselling methods to ultimately improve pts’ quality of life while on tx. HCPs may play a critical role in developing and disseminating fatigue management initiatives. [Table: see text]
Efficacy and safety of docetaxel (D) vs androgen-receptor signaling inhibitors (ARSi) as second-line therapy (Rx) after progression on alternative ARSi as first-line Rx for patients who are elderly (≥75 years old) with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter international database: A SPARTACUSS–Meet-URO 26 study.
Authors: Gennusa Vincenzo , Saieva Calogero , Lee-Ying Richard M. , Nuzzo Pier Vitale , Spinelli Gian Paolo , Zanardi Elisa , Fotia Giuseppe , Rossetti Sabrina , Valenca Loana Bueno , Patrikidou Anna , Andrade Livia , Pereira Mestre Ricardo , Fornarini Giuseppe , Procopio Giuseppe , Santini Daniele , Sweeney Christopher , Heng Daniel Yick Chin , De Giorgi Ugo , Russo Antonio , Francini Edoardo
Published: March 2023

166

Background: About 2/3 of all prostate cancer (PCa) deaths occur in patients aged ≥75, who are frequently diagnosed with advanced PCa. ARSi abiraterone acetate (AA) and enzalutamide (E) are the most common 1st line Rx for patients with mCRPC. Yet, the optimal treatment sequence for the elderly ≥75 after ARSi failure is still unclear. Methods: Using available medical records, patients aged ≥75 who started ARSi as 1st line Rx for mCRPC within January 2015 - April 2019 and, upon progression, 2nd line alternative ARSi or D were identified from the IRB approved hospital registries of 10 centers in Europe, North and South America. Patients were categorized by type of 2nd line Rx for mCRPC into cohorts AA/E and D. Primary endpoints were overall survival (OS) from 1st line AA/E start, OS and radiographic progression-free survival (rPFS) from 2nd line Rx start, and safety. The Kaplan Meier method was used to calculate endpoint distributions and medians (95% CI). Results: Of the 122 patients identified, 57 (46.7%) had AA/E and 65 (53.3%) D, as 2nd line Rx for mCRPC. Median follow-up was 26.3 months (95% CI, 23.1-27.9 months). Cohort AA/E tended to be older (81 vs 78 years; p=0.001) and with high-volume disease (45.5% vs 25.0%; p=0.022) compared to cohort D. No significant difference in OS from 1st line ARSi onset and OS or rPFS from 2nd line Rx start was found between the 2 cohorts. Cohort AA/E had longer rPFS than cohort D, albeit not significant (18.5 vs 12.0 months; p=0.13). Rates of adverse events (AEs) of any grade (42.1 vs 53.8; p=0.21) and AEs of grade ≥3 (19.3% vs 18.5%; p=1.0) did not show significant differences between the 2 cohorts. Conclusions: Within the limitations of small cohorts and retrospective design, treatment sequences with 2nd line AA/E or D after failure of 1st line alternative ARSi for mCRPC showed similar efficacy and safety in the elderly ≥75 years old.
Outcomes of post-progression therapies in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) progressing after docetaxel (DOC): Real-world data from an Italian multicenter observational study (ECHOS trial).
Authors: Caffo Orazio , Maruzzo Marco , Samuelly Alessandro , Facchini Gaetano , Zanardi Elisa , Nicodemo Maurizio , Ermacora Paola , Sorarù Mariella , Galli Luca , Cattrini Carlo , Borsellino Nicolo , Buti Sebastiano , Rebuzzi Sara Elena , Iacovelli Roberto , Rametta Alessandro , Calvani Nicola , Giordano Monica , Farnesi Azzurra , Fratino Lucia , Basso Umberto
Published: March 2023

171

Background: The introduction of DOC in mCSPC raises the issue concerning the best therapeutic strategy after pts’ progression. Different options are available: a switch strategy with an androgen receptor signaling inhibitor (ARSI), an alternative chemotherapy-based strategy based on cabazitaxel (CABA), or a re-challenge strategy by using DOC again. In this view, it could be of interest to describe the outcomes of post-progression strategies adopted in the real-world. From 2014, ECHOS multicenter study is collecting real world data from mCSPC pts in Italy. Here, we present post-progression preliminary findings of 568 pts treated with DOC and enrolled in the study within 31 December 2021. Methods: We reviewed the clinical records of the mCSPC pts treated with DOC in 34 Italian Institutions. For each pt we recorded pre- and post-DOC clinical history, baseline characteristics, treatment details and clinical outcomes. Results: Among the 568 pts, after a median follow-up of 22 mos, 389 pts experienced disease progression and 227 died. The progression occurred after a median of 10.4 mos (range 0.3-62.1). Among the progressed pts, 47 did not received further active treatment, while 342 received at least one systemic treatment after progression. The most frequent post-progression treatment was ARSI (73.1%), followed by CABA (19%), combination of ARSI and PARP inhibitors within clinical trials (2.6%), DOC re-challenge (2.1%), platinum-based chemotherapy (1.8%), and radium 223 (0.9%). The outcomes of the first-line agents and the number of subsequent administered life-prolonging agents (LPA) are described. The length of disease control obtained with DOC influenced the duration of first post-progression therapy: in pts who progressed after DOC within 10.4 mos, the duration was significantly shorter than in pts with later disease progression (5.9 mos vs 9.8 mos, p < 0.0001). Noteworthy, pts with more aggressive disease leading to a faster progression received more frequently CABA than ARSI: disease progression after DOC in CABA group and in ARSI group occurred with a median of 9.1 mos and 13.2 mos, respectively (p = 0.002). Conclusions: This is one of the largest real-world report on the outcomes of first post-progression therapies after DOC in mCSPC pts. We showed that ARSI-based therapy is the most common strategy adopted after DOC progression. Our findings suggested a different first post-progression strategy according to the time of post-DOC progression onset. [Table: see text]
Phase 1/2 study of EPI-7386 in combination with enzalutamide (enz) compared with enz alone in subjects with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Laccetti Andrew Leonard , Chatta Gurkamal S. , Iannotti Nicholas , Kyriakopoulos Christos , Villaluna Karen , Le Moigne Ronan , Cesano Alessandra
Published: March 2023

179

Background: EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain (NTD) of the AR while effectively blocking transcription despite AR resistance mechanisms driven by the ligand-binding domain (LBD), including point mutations and splice variants. Preclinical models demonstrate the combination of EPI-7386 with enzalutamide (enz) results in a deeper blockade of the AR pathway (per RNAseq and ChIPseq data) and greater antitumor activity, prompting initiation of this trial. Methods: This Phase 1/2 multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC pts on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy allowed). Phase 1 (P1) of the trial examines escalating doses of EPI-7386 in combination with a fixed dose of enz. The primary and secondary endpoints of P1 are to evaluate the safety and pharmacokinetics (PK) aspects of EPI-7386 and enz when administered in combination to establish the recommended Phase 2 combination doses (RP2CDs) and address any possible drug-drug interactions. Once the RP2CDs are established, Phase 2 of the trial will commence as a two -arm, 2:1 randomized trial evaluating the antitumor activity of EPI-7386 in combination with enz versus enz alone. Results: Seven pts have been enrolled in the first 2 cohorts: 3 in cohort 1 (600 mg QD EPI-7386 + 120 mg QD enz) and 4 in cohort 2 (800 mg QD EPI-7386 + 120 mg QD enz). No DLTs were observed, and the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrated enz exposure was minimally impacted by EPI-7386, while, as expected, EPI-7386 exposure was reduced 60-80% by enz (well-established CYP3A4 inducer). The observed EPI-7386 exposures remained in the clinically relevant range suggested by preclinical xenograft studies. 4/6 evaluable patients showed a PSA decrease >90% at/before week 12 regardless of the pt’s previous chemotherapy status and 5/6 evaluable patients achieved a PSA decrease of at least 85%; all 6 patients showed stable disease by imaging. Conclusions: With no safety concerns from cohorts 1 and 2, cohort 3 is enrolling at 600 mg BID EPI-7386 + 120 mg QD enz to assess if the exposure of EPI-7386 can be further increased in light of the augmented metabolism of the drug induced by enz. Clinical trial information: NCT05075577 .
Randomized phase II study of olaparib (Ola) maintenance following cabazitaxel-carboplatin induction chemotherapy (CabCarb) in men with aggressive variant prostate cancer (AVPC).
Authors: Pilié Patrick Glen , Slack Tidwell Rebecca , Viscuse Paul Vincent , Subudhi Sumit Kumar , Corn Paul Gettys , Tu Shi-Ming , Araujo John C. , Zurita Amado J. , Wang Jennifer , Efstathiou Eleni , Deinert Jessica , Logothetis Christopher , Thompson Timothy C. , Aparicio Ana
Published: March 2023

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Background: An aggressive subset of prostate cancers (AVPC) respond poorly to androgen signaling inhibitors, have limited therapeutic options and a dismal prognosis. Preclinical models of AVPC display functional alterations in DNA damage response (DDR) pathways linked to platinum and PARP inhibitor (PARPi) sensitivity. We hypothesized that PARPi (ola) maintenance following CabCarb would improve the progression free survival (PFS) of men with AVPC. We performed a tissue-rich randomized trial for men with AVPC to address this hypothesis and unravel the heterogeneity of AVPC by linking genomic and transcriptomic analyses with clinical outcomes. Methods: In a single-institution study, men with CRPC meeting ≥ 1 of 9 AVPC criteria and ECOG performance status (PS) of 0-2 received 6 cycles of Cab 20-25mg/m2 and Carbo (AUC 3-4). Men completing 6 cycles without progressive disease (PD) were randomized 2:1 to Ola 300mg BID vs. observation (Obs). The primary endpoint is to estimate PFS in those randomized and we aimed to detect a difference of 3.9 vs. 7.8 months. Subgroup comparisons between patients who had PD prior to randomization (platinum-resistant) vs. those randomized (platinum sensitive) were made with chi-square tests for categorical baseline characteristics, and Kruskal-Wallis test for continuous measures. Results: 96 patients started CabCarb. Their median age was 67 years (43-86), most were white/non-Hispanic (74%), had an ECOG score of 0 (64%), bone metastases (79%), and no prior docetaxel therapy (59%). Of the 96, 7 (7.3%) went off study for reasons unrelated to PD and 36 (37.5%) had PD prior to randomization. Patients with PD prior to randomization were more likely at baseline to have received prior docetaxel (59% vs. 29%; p=0.004), have bone metastases (92% vs. 71%; p=0.03), have lower hemoglobin (11.4 vs. 12. 4; p=0.02), higher LDH (359 vs. 260; p=0.01), lower albumin (4.0 vs. 4.2; p=0.04), and higher AlkPhos (181.5 vs. 98.5; p=0.01) compared to patients who went on to randomization. With a median follow up time of 38.9 months post randomization, the median PFS was 2.3 months (95% confidence interval: 1.3, 4.6 months) for Observation and 4.9 (3.5, 6.3) months with Olaparib (p=0.12). The median OS was 16.2 (6.8, 26.4) for observation and 15.3 (10.2, 28.4) months with Olaparib (p=0.56). Conclusions: These data highlight the heterogeneity within the AVPC subset. Ongoing molecular analyses of sequential liquid and tumor tissue will illuminate the underpinnings of this heterogeneity and identify targets for additional combinatorial strategies. Clinical trial information: NCT03263650 .
Prognostic value of pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.
Authors: Wang Zhipeng , Liu Haoyang , Zhao Jinge , Shen Pengfei , Zeng Hao
Published: March 2023

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Background: The aim of this study was to explore the prognostic value of the lung immune prognostic index (LIPI) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively analyzed data of 502 mHSPC patients primarily treated with maximal androgen blockade and 158 mCRPC patients receiving abiraterone. All cases were classified into the LIPI-Good, LIPI-Intermediate, and LIPI-Poor groups based on their LIPI score calculated by the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase. The potential of LIPI in predicting mCRPC-free survival (CFS), PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) were analyzed. A propensity score matching (PSM) methodology was performed to balance the baseline factors of different groups. Results: In the mHSPC cohort, patients of the LIPI-Good (mCFS: 25.7 mo; mOS: 93.3 mo), LIPI-Intermediate (mCFS: 14.8 mo; mOS: 51.9 mo) and LIPI-Poor group (mCFS: 6.8 mo; mOS: 18.5 mo) had sequentially worse clinical outcomes (P<0.001 for all pairwise comparisons). The results remain consistent after PSM. Multivariate Cox regression further confirmed that LIPI was an independent predictor of survival outcomes. Subgroup analysis verified that LIPI was associated with unfavorable prognosis in all subgroups except for cases with visceral metastases or receiving abiraterone/docetaxel. As for patients with CRPC receiving abiraterone, LIPI was also an indicator of poor prognosis. Specifically, cases in the LIPI-Good, LIPI-Intermediate and LIPI-Poor group had a ladder-shaped worse PSA response (71.4% [50/70] vs. 56.5% [39/69] vs. 36.8% [7/12], P=0.015), PSA-PFS (14.9- vs. 9.3 vs. 3.1 mo, P<0.001) and OS (14.6- vs. 32.3- vs. 53.4 mo, P<0.001). The results were robust even after PSM. Multivariate Cox regression confirmed that LIPI was an independent prognosticator of abiraterone. Conclusions: This study demonstrated that baseline LIPI was a significant prognostic biomarker for both mHSPC and mCRPC patients and could potentially facilitate risk classification and treatment-decision making in clinical practice.
Prevalence of HRR gene mutations in patients with metastatic castration-resistant prostate cancer: Germline results from the Latin-American observational study PROSPECT.
Authors: Manneh Kopp Ray , Alaez Verson Carmen , Angel Martin , Delgado Arturo , Isaacsson Velho Pedro H , Manduley Alejandro , Barbieri Melissa , Vargas Carmen , Gonzalez Francisco , Barata Pedro C.
Published: March 2023

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Background: Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, and 20% to 30% of patients harbor alterations in homologous recombination repair (HRR) genes. However, data regarding the genetic profile of mCRPC in Latin American populations are scarce. This study determined the prevalence of HRR gene mutations in Latin American patients with mCRPC to better understand this population and guide future policies. The interim analysis herein reports results focused on germline alterations only. Methods: PROSPECT (NCT04962880) is a cross-sectional, non-interventional, multicenter study. Patients were adults (≥18 years) diagnosed with mCRPC from November 2020 to October 2021 at centers in Argentina, Brazil, Colombia, Costa Rica, Mexico, Panama, and Peru. Diagnoses were confirmed by laboratory testing (PSA and/or testosterone levels) or imaging (X-ray, CT, MRI, or PET scan). All patients provided written informed consent. Blood samples were assayed to determine the prevalence of germline mutations in HRR genes in the participating countries using the AmoyDx HANDLE HRR Next Generation Sequence 32 genes Panel (AmoyDx, Xiamen, China). Results: Overall, 388 participants with a median age of 70 years (range: 49‒89) were included in this study, including 184 Hispanic (47.4%), 101 White (26%), 40 Mestizo (10.3%), 11 African American (2.8%), 2 Asian (0.5%), and 50 “other” (12.9%) patients. Over a third of them (n=151, 38.9%) had a family history of cancer. Median time since prostate cancer diagnosis was 3 years (range: 0‒23) and 2 years (range: 0‒22) since mCRPC diagnosis. Metastases were most frequently localized to the bones (59.6%). The patients’ ECOG status was either 0 (173/365; 47.4%) or 1 (192/365; 52.6%). Among the 167 patients that received treatment, most received androgen deprivation therapy alone (43.7%) or with radiotherapy (21.6%). Overall, 25/381 patients (6.56%) had germline HRR mutations. The 5 most frequently mutated HRR genes were BRCA2 (16%), ATM (12%), CHEK2 (12%), BRIP1 (8%) and HOXB13 (8%). Conclusions: The prevalence of germline HRR mutations found in this multinational Latin American population was lower than expected compared to previously reported rates ranging from 8% to 12% from other countries. Additionally, the most frequently mutated HRR genes differed from those from major trials including PROfound (NCT02987543). Clinical trial information: NCT04962880 . [Table: see text]
Association of obesity with tumor differential gene expression and gene set enrichment pathways in advanced prostate adenocarcinoma (PCa).
Authors: Mathew Thomas Vinay , Chigarira Beverly , Gebrael Georges , Sayegh Nicolas , Tripathi Nishita , Jo Yeonjung , Nussenzveig Roberto , Sahu Kamal Kant Kant , Li Haoran , Tandar Clara , Goel Divyam , McFarland Taylor Ryan , Brundage James , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: March 2023

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Background: Increased Body Mass Index (BMI) has been linked to increased prostate cancer incidence, recurrence, and mortality (PMID: 35538398). Herein, we sought to investigate the underlying differences in gene expression profiles based on BMI in patients (pts) with PCa. Methods: In this IRB-approved retrospective study, eligibility criteria included histologically confirmed PCa and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA-certified lab. Pts were categorized into two cohorts: obese (Ob, BMI≥30) and non-obese (non-Ob, BMI<30). BMI at the time of diagnosis of PCa was used for analysis. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values (q values) for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: 60 pts were eligible, of which 22 were Ob and 38 were non-Ob. Tumor tissues from Ob pts had an increased expression of the heme metabolism, androgen-response, protein secretion, fatty acid, and bile metabolism pathways. Non-Ob pts had a significantly higher expression of genes involved in the inflammation pathways (interferon-alpha & TNF alpha pathways). Normalized enrichment scores are reported. Differential individual gene expression profiles will be presented at the meeting. Conclusions: Our study showed upregulation of distinct genomic pathways in Ob pts with prostate cancer which may help personalize medicine and guide further drug development. These hypothesis-generating data require external validation. [Table: see text]
Machine-learning to predict utility of circulating tumor DNA (ctDNA) for somatic genotyping.
Authors: Herberts Cameron , Tu Wilson , Fonseca Nicolette M. , Maurice-Dror Corinne , Khalaf Daniel Joseph , Annala Matti , Chi Kim N. , Wyatt Alexander William
Published: March 2023

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Background: ctDNA genotyping is increasingly used to evaluate patient eligibility for genomics-driven treatments ( e.g., PARP inhibitors) in metastatic castration-resistant prostate cancer (mCRPC), but low ctDNA-fraction (ctDNA%) causes false negatives and is unpredictable. We investigated whether a machine-learning model exploiting routine clinical prognostic markers can predict if a mCRPC patient will have sufficient ctDNA% for informative ctDNA testing. Methods: We analysed plasma cell-free DNA (cfDNA) collected at baseline prior to first-line therapy from 463 consecutive mCRPC patients. ctDNA% was quantified using somatic allele frequencies and genome-wide copy number profiles via deep targeted sequencing. We built an XGBoost model (70:30 train-test split) using 18 clinical factors to predict synchronously measured ctDNA% (binary classification >2% or ≤2%, i.e., the conventional ctDNA% limit of detection for mutations employed by commercial tests), with performance evaluated using area under the curve (AUC) of receiver operating characteristics. Results: Median age was 73 (range: 45-98) and 86% of patients had ECOG 0-1. Median ctDNA% was 5% (range: 0-89%) and correlated with serum and radiographic metrics of disease burden, including total cfDNA concentration (ng/mL of plasma, reflecting cfDNA released by both normal and tumor cells; Spearman ρ=0.55), alkaline phosphatase (ALP) per upper limit of normal (ULN) ( ρ=0.46), lactate dehydrogenase (LDH) per ULN ( ρ=0.41), PSA ( ρ=0.3), presence of liver metastases, and ≥10 bone lesions. We trained an XGBoost model incorporating these and 13 additional clinical factors achieving an AUC for ctDNA >2% of 0.83 (F1 score: 0.79). SHAP interpretability scores indicated that cfDNA concentration most strongly informed prediction of ctDNA >2%, followed by ALP/ULN and PSA—consistent with our prior bivariate rank correlations—whereas features associated with initial prostate cancer diagnosis (Gleason Grade Group, de novo versus metachronous M1 disease) were less informative. Recognizing that comprehensive and standardised clinical annotation is not always available in real-world settings, we built a secondary parsimonious ctDNA%-prediction tool restricted to 8 highly informative and clinically practical factors (cfDNA concentration, ALP/ULN, LDH/ULN, PSA, albumin, ECOG, liver metastases, lung metastases) and flexible to incomplete input data, achieving a comparable AUC for ctDNA>2% of 0.76. Conclusions: Our results demonstrate the feasibility of a machine learning framework to estimate ctDNA% in patients with mCRPC. This point-of-care tool would enable prioritisation of mCRPC patients for ctDNA somatic genotyping with a predicted ctDNA >2%, versus tissue or germline-only testing in patients with a predicted ctDNA ≤2%.
Analysis of TP53 gain of function mutations in metastatic castration-resistant prostate cancer.
Authors: Sweeney Patrick L , Lanka Sree M , Jang Albert , Gupta Kanika , Caputo Sydney , Casado Crystal , Huang Minqi , Pocha Olivia , Hawkins Maddie , Lieberman Alexandra , Schwartz Jennifer , Jaeger Ellen B. , Miller Patrick , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Ledet Elisa M. , Sartor A. Oliver
Published: March 2023

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Background: TP53, an oncogene implicated in the development of many malignancies, is commonly altered in mCRPC. Gain-of-function mutations in TP53 confer increased oncogenic properties of this gene and play a role in mCRPC. The goal of this study was to characterize somatic TP53 mutations, specifically gain-of-function mutations, in the ctDNA of mCRPC patients in the context of prior therapies. Methods: A retrospective analysis of mCRPC patients at Tulane Cancer Center between 2015-2022 was performed. All patients had ctDNA testing performed with the Guardant360 multigene panel assay. Clinical annotation including initial diagnosis, staging, treatment history, and family history were obtained. TP53 mutations were classified based on existing published functional studies and/or in silico evaluation. Statistical analyses were performed with Fisher's exact and Chi-squared tests where appropriate. Results: 338 mCRPC patients with ctDNA testing were included in this analysis. 76 patients had no prior treatment with either abiraterone or enzalutamide, while 262 patients had been treated with abiraterone and/or enzalutamide. Somatic TP53 mutations were similar in frequency between those with or without abiraterone/enzalutamide pretreatment; 46% (35/76) of patients in the abiraterone/enzalutamide naïve subset had a somatic TP53 mutation, compared to 41% (108/262) of patients previously treated with abiraterone and/or enzalutamide. Only 9% (7/76) of abiraterone/enzalutamide naïve patients had a TP53 gain-of-function mutation, compared to 19% (49/262) of patients previously treated with one or both drugs ( p = 0.05). The most common type of TP53 mutation was loss-of-function. There were no significant associations between TP 53 mutations and occurrence of other common mutations. Conclusions: mCRPC patients with prior treatment of abiraterone and/or enzalutamide were significantly more likely to have a gain-of-function TP53 mutation. Further studies are needed to investigate therapeutic implications of these findings.