-
PET Clinics Jun 2024The 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography combined with computed tomography (PET/CT) has contributed to outcome improvement of patients with... (Review)
Review
The 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography combined with computed tomography (PET/CT) has contributed to outcome improvement of patients with lymphoma. The use of [F]FDG PET/CT for staging and response assessment is successfully applied both in routine clinical practice and in clinical trials. The challenges lie in enhancing the outcomes of lymphoma patients, particularly those with advanced or refractory/relapsed disease, and to minimize the long-term toxicity associated with treatments, including radiation therapy. The objective of this review article is to present contemporary data on the use of [F]FDG PET/CT for treatment assessment of aggressive lymphomas.
PubMed: 38945737
DOI: 10.1016/j.cpet.2024.05.001 -
Risk Analysis : An Official Publication... Jun 2024This article presents a risk analysis of large language models (LLMs), a type of "generative" artificial intelligence (AI) system that produces text, commonly in...
This article presents a risk analysis of large language models (LLMs), a type of "generative" artificial intelligence (AI) system that produces text, commonly in response to textual inputs from human users. The article is specifically focused on the risk of LLMs causing an extreme catastrophe in which they do something akin to taking over the world and killing everyone. The possibility of LLM takeover catastrophe has been a major point of public discussion since the recent release of remarkably capable LLMs such as ChatGPT and GPT-4. This arguably marks the first time when actual AI systems (and not hypothetical future systems) have sparked concern about takeover catastrophe. The article's analysis compares (A) characteristics of AI systems that may be needed for takeover, as identified in prior theoretical literature on AI takeover risk, with (B) characteristics observed in current LLMs. This comparison reveals that the capabilities of current LLMs appear to fall well short of what may be needed for takeover catastrophe. Future LLMs may be similarly incapable due to fundamental limitations of deep learning algorithms. However, divided expert opinion on deep learning and surprise capabilities found in current LLMs suggests some risk of takeover catastrophe from future LLMs. LLM governance should monitor for changes in takeover characteristics and be prepared to proceed more aggressively if warning signs emerge. Unless and until such signs emerge, more aggressive governance measures may be unwarranted.
PubMed: 38945529
DOI: 10.1111/risa.14353 -
Toxicology and Applied Pharmacology Jun 2024Colitis-associated cancer (CAC) is an aggressive subtype of colorectal cancer that can develop in ulcerative colitis patients and is driven by chronic inflammation and...
Colitis-associated cancer (CAC) is an aggressive subtype of colorectal cancer that can develop in ulcerative colitis patients and is driven by chronic inflammation and oxidative stress. Current chemotherapy for CAC, based on 5-fluorouracil and oxalipltin, is not fully effective and displays severe side effects, prompting the search for alternative therapies. Dimethylfumarate (DMF), an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2), is a potent antioxidant and immunomodelatrory drug used in the treatment of multiple sclerosis and showed a strong anti-inflammatory effect on experimental colitis. Here, we investigated the chemotherapeutic effect of DMF on an experimental model of CAC. Male NMRI mice were given two subcutaneous injections of 1,2 Dimethylhydrazine (DMH), followed by three cycles of dextran sulfate sodium (DSS). Low-dose (DMF30) and high-dose of DMF (DMF100) or oxaliplatin (OXA) were administered from the 8th to 12th week of the experiment, and then the colon tissues were analysed histologically and biochemically. DMH/DSS induced dysplastic aberrant crypt foci (ACF), oxidative stress, and severe colonic inflammation, with a predominance of pro-inflammatory M1 macrophages. As OXA, DMF30 reduced ACF multiplicity and crypt dysplasia, but further restored redox status, and reduced colitis severity by shifting macrophages towards the anti-inflammatory M2 phenotype. Surprisingly, DMF100 exacerbated ACF multiplicity, oxidative stress, and colon inflammation, likely through NRF2 and p53 overexpression in colonic inflammatory cells. DMF had a dual effect on CAC. At low dose, DMF is chemotherapeutic and acts as an antioxidant and immunomodulator, whereas at high dose, DMF is pro-oxidant and exacerbates colitis-associated cancer.
PubMed: 38945373
DOI: 10.1016/j.taap.2024.117018 -
Cancer Letters Jun 2024The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This...
The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
PubMed: 38945201
DOI: 10.1016/j.canlet.2024.217090 -
International Immunopharmacology Jun 2024Hepatic ischemia-reperfusion (I/R) injury is a clinically fundamental phenomenon that occurs through liver resection surgery, trauma, shock, and transplantation. (Review)
Review
BACKGROUND
Hepatic ischemia-reperfusion (I/R) injury is a clinically fundamental phenomenon that occurs through liver resection surgery, trauma, shock, and transplantation.
AIMS OF THE REVIEW
This review article affords an expanded and comprehensive overview of various natural herbal ingredients that have demonstrated hepatoprotective effects against I/R injury through preclinical studies in animal models.
MATERIALS AND METHODS
For the objective of this investigation, an extensive examination was carried out utilizing diverse scientific databases involving PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate. The investigation was conducted based on specific identifiable terms, such as hepatic ischemia/reperfusion injury, liver resection and transplantation, cytokines, inflammation, NF-kB, interleukins, herbs, plants, natural ingredients, phenolic extract, and aqueous extract.
RESULTS
Bioactive ingredients derived from ginseng, curcumin, resveratrol, epigallocatechin gallate, quercetin, lycopene, punicalagin, crocin, celastrol, andrographolide, silymarin, and others and their effects on hepatic IRI were discussed. The specific mechanisms of action, signaling pathways, and clinical relevance for attenuation of liver enzymes, cytokine production, immune cell infiltration, oxidative damage, and cell death signaling in rodent studies are analyzed in depth. Their complex molecular actions involve modulation of pathways like TLR4, NF-κB, Nrf2, Bcl-2 family proteins, and others.
CONCLUSION
The natural ingredients have promising values in the protection and treatment of various chronic aggressive clinical conditions, and that need to be evaluated on humans by clinical studies.
PubMed: 38944946
DOI: 10.1016/j.intimp.2024.112445 -
Cell Reports Jun 2024Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with...
Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy.
PubMed: 38944837
DOI: 10.1016/j.celrep.2024.114409 -
Journal of Extracellular Vesicles Jul 2024Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains...
Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains poorly understood. Here, we demonstrate the involvement of β-hexosaminidase B (HEXB) in mediating EV release in response to oxidative stress, thereby promoting the development of hepatocellular carcinoma (HCC). Mechanistically, reactive oxygen species (ROS) stimulate the nuclear translocation of transcription factor EB (TFEB), leading to the upregulation of both HEXB and its antisense lncRNA HEXB-AS. HEXB-AS can bind HEXB to form a protein/RNA complex, which elevates the protein stability of HEXB. The stabilized HEXB interacts with lysosome-associated membrane glycoprotein 1 (LAMP1), disrupting lysosome-multivesicular body (MVB) fusion, which protects EVs from degradation. Knockdown of HEXB efficiently inhibits EV release and curbs HCC growth both in vitro and in vivo. Moreover, targeting HEXB by M-31850 significantly inhibits HCC growth, especially when combined with GW4869, an inhibitor of exosome release. Our results underscore the critical role of HEXB as a modulator that promotes EV release during HCC development.
Topics: Extracellular Vesicles; Carcinoma, Hepatocellular; Animals; Oxidative Stress; Humans; Liver Neoplasms; Mice; Up-Regulation; Cell Line, Tumor; Cell Proliferation; RNA, Long Noncoding; Reactive Oxygen Species; Gene Expression Regulation, Neoplastic; Male; Mice, Nude
PubMed: 38944674
DOI: 10.1002/jev2.12468 -
Urologic Oncology Jun 2024Penile cancer (PeCa) is a rare disease. HPV infection, smoking, phimosis, and lichen sclerosus represent well-known associated risk factors.
BACKGROUND
Penile cancer (PeCa) is a rare disease. HPV infection, smoking, phimosis, and lichen sclerosus represent well-known associated risk factors.
OBJECTIVES
Primary aim of our study is to evaluate the incidence and risk factors of PeCa and to outline the adopted diagnostic and therapeutic approaches. Secondary aim is to investigate risk factors associated with aggressive disease and to identify the complications arising from its surgical treatment.
MATERIALS AND METHODS
We conducted a retrospective analysis using the PearlDiver™ Mariner database, from January 1, 2011, to December 31, 2021, identifying all patients diagnosed with PeCa and PeIN, evaluating comorbidities, risk factors, and social and economic conditions. We evaluated the imaging modalities employed for staging as well as the treatment strategies. Finally, we evaluated the most frequent complications associated with inguinal lymphadenectomy (ILND).
RESULTS
During the study period, 17,494 patients were diagnosed with PeCa and 5,965 with penile intraepithelial neoplasia (PeIN). US was the most frequently utilized imaging modality, followed by PET and PET/CT. Use of CT and MRI was around 5%. Surgical treatment was the predominant strategy, utilized in 31.3% of PeCa and 22.9% of PeIN. Wide Local Excision/Glansectomy emerged as the most common surgical procedures. MLR analysis identified smoking as a risk factor for metastatic PeCa (OR; 95% CI = 1.49; 1.379-1.609), HPV infections were associated with a 35% decrease in risk (OR; 95% CI = 0.65; 0.562-0.744) (all P < 0.001). Lichen sclerosus and phimosis were associated with a doubled risk of demolitive surgery. Approximately 40% of patients experienced complications associated with ILND.
CONCLUSION
Despite advances in PeCa management, there's no significant move toward more conservative treatments. Surgical treatments are still marked by high rates of complications, potentially affect the sexual and psychosocial health of patients. These issues may foster a tendency toward avoidance behaviors, contributing to a delayed clinical presentation and treatment.
PubMed: 38944595
DOI: 10.1016/j.urolonc.2024.05.013 -
The Surgical Clinics of North America Aug 2024Thyroid carcinoma of follicular cell origin exists on a histopathologic and clinical spectrum. The authors focus on the category of tumors that fall between the very... (Review)
Review
Thyroid carcinoma of follicular cell origin exists on a histopathologic and clinical spectrum. The authors focus on the category of tumors that fall between the very favorable well-differentiated thyroid carcinomas and the very unfavorable anaplastic thyroid carcinomas. These intermediately aggressive tumors include poorly differentiated thyroid carcinoma and the newly defined differentiated high-grade thyroid carcinoma. Both diagnoses require certain histopathologic requirements be met in order to accurately identify these tumors post-operatively. Management remains primarily surgical though adjunctive treatments such as molecular targeted therapies (eg, tyrosine kinase inhibitors) and differentiation therapy (to restore tumor response to radioactive iodine) are also becoming available.
Topics: Humans; Thyroid Neoplasms; Thyroidectomy; Neoplasm Grading; Adenocarcinoma, Follicular; Thyroid Carcinoma, Anaplastic
PubMed: 38944496
DOI: 10.1016/j.suc.2024.02.005 -
Thoracic Surgery Clinics Aug 2024Abuse, bullying, harassment, and discrimination are prominent workplace occurrences within cardiothoracic (CT) surgery that cause burnout and threaten the well-being of... (Review)
Review
Abuse, bullying, harassment, and discrimination are prominent workplace occurrences within cardiothoracic (CT) surgery that cause burnout and threaten the well-being of surgeons. Under-represented and marginalized groups experience higher incidences of these negative events, and CT surgery is one of the least diverse specialties. The CT surgery workforce and institutional leadership must prioritize mentorship, sponsorship, and allyship to promote a diverse and healthy specialty for surgeon recruitment, growth, and job satisfaction.
Topics: Humans; Bullying; Thoracic Surgery; Surgeons; Burnout, Professional; Job Satisfaction
PubMed: 38944451
DOI: 10.1016/j.thorsurg.2024.04.001