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1.
Nature ; 603(7900): 290-296, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35197631

RESUMEN

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.


Asunto(s)
Población Negra , ADN Antiguo , Genética de Población , África del Sur del Sahara , Arqueología , Población Negra/genética , Población Negra/historia , ADN Antiguo/análisis , Flujo Génico/genética , Genoma Humano/genética , Historia Antigua , Humanos
2.
Proc Natl Acad Sci U S A ; 120(14): e2220413120, 2023 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-36972439

RESUMEN

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Gástricas , Humanos , Animales , Ratones , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/radioterapia , Neoplasias Gástricas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Preparaciones Farmacéuticas , Receptor ErbB-2/metabolismo , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Lovastatina/farmacología , Lovastatina/uso terapéutico , Línea Celular Tumoral
3.
Proc Natl Acad Sci U S A ; 119(27): e2203820119, 2022 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-35759660

RESUMEN

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (177Lu)-labeled DLL3-targeting antibody SC16 (177Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with 177Lu to produce 177Lu-DTPA-SC16. Specificity and selectivity of 177Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of 177Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft-bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. 177Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of 177Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, 177Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that 177Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma Neuroendocrino , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Neoplasias de la Próstata , Radioinmunoterapia , Animales , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Neuroendocrino/radioterapia , Quelantes/química , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/inmunología , Ligandos , Lutecio , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , Ácido Pentético/química , Neoplasias de la Próstata/radioterapia , Radioisótopos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Lancet Oncol ; 25(6): e250-e259, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38821099

RESUMEN

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.


Asunto(s)
Oncología Médica , Medicina Nuclear , Radiofármacos , Humanos , Radiofármacos/uso terapéutico , Radiofármacos/provisión & distribución , Medicina Nuclear/educación , Medicina Nuclear/tendencias , Neoplasias/radioterapia , Neoplasias/terapia , Fuerza Laboral en Salud/tendencias
5.
Lancet Oncol ; 25(8): 1015-1024, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38950555

RESUMEN

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular , Neoplasias Pulmonares , Proteínas de la Membrana , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Radioisótopos , Circonio , Humanos , Masculino , Persona de Mediana Edad , Anciano , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/tratamiento farmacológico , Femenino , Deferoxamina/química , Inmunoconjugados/farmacocinética , Clasificación del Tumor , Radiofármacos , Adulto , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/administración & dosificación , Anciano de 80 o más Años , Benzodiazepinonas , Anticuerpos Monoclonales Humanizados
6.
Lancet Oncol ; 25(6): e260-e269, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38821100

RESUMEN

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer.


Asunto(s)
Radiofármacos , Nanomedicina Teranóstica , Humanos , Radiofármacos/uso terapéutico , Neoplasias/terapia , Medicina de Precisión
7.
Lancet Oncol ; 25(6): e236-e249, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38821098

RESUMEN

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.


Asunto(s)
Neoplasias , Radiofármacos , Humanos , Radiofármacos/uso terapéutico , Neoplasias/terapia , Neoplasias/radioterapia , Oncología Médica , Inteligencia Artificial
8.
Lancet Oncol ; 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39362232

RESUMEN

Following on from the 2015 Lancet Oncology Commission on expanding global access to radiotherapy, Radiotherapy and theranostics: a Lancet Oncology Commission was created to assess the access and availability of radiotherapy to date and to address the important issue of access to the promising field of theranostics at a global level. A marked disparity in the availability of radiotherapy machines between high-income countries and low-income and middle-income countries (LMICs) has been identified previously and remains a major problem. The availability of a suitably trained and credentialled workforce has also been highlighted as a major limiting factor to effective implementation of radiotherapy, particularly in LMICs. We investigated initiatives that could mitigate these issues in radiotherapy, such as extended treatment hours, hypofractionation protocols, and new technologies. The broad implementation of hypofractionation techniques compared with conventional radiotherapy in prostate cancer and breast cancer was projected to provide radiotherapy for an additional 2·2 million patients (0·8 million patients with prostate cancer and 1·4 million patients with breast cancer) with existing resources, highlighting the importance of implementing new technologies in LMICs. A global survey undertaken for this Commission revealed that use of radiopharmaceutical therapy-other than 131I-was highly variable in high-income countries and LMICs, with supply chains, workforces, and regulatory issues affecting access and availability. The capacity for radioisotope production was highlighted as a key issue, and training and credentialling of health professionals involved in theranostics is required to ensure equitable access and availability for patient treatment. New initiatives-such as the International Atomic Energy Agency's Rays of Hope programme-and interest by international development banks in investing in radiotherapy should be supported by health-care systems and governments, and extended to accelerate the momentum generated by recognising global disparities in access to radiotherapy. In this Commission, we propose actions and investments that could enhance access to radiotherapy and theranostics worldwide, particularly in LMICs, to realise health and economic benefits and reduce the burden of cancer by accessing these treatments.

9.
Clin Gastroenterol Hepatol ; 22(6): 1170-1180, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38154727

RESUMEN

Significant advances in artificial intelligence (AI) over the past decade potentially may lead to dramatic effects on clinical practice. Digitized histology represents an area ripe for AI implementation. We describe several current needs within the world of gastrointestinal histopathology, and outline, using currently studied models, how AI potentially can address them. We also highlight pitfalls as AI makes inroads into clinical practice.


Asunto(s)
Inteligencia Artificial , Enfermedades Gastrointestinales , Humanos , Enfermedades Gastrointestinales/patología , Enfermedades Gastrointestinales/diagnóstico , Tracto Gastrointestinal/patología , Histocitoquímica/métodos
10.
Artículo en Inglés | MEDLINE | ID: mdl-38940841

RESUMEN

PURPOSE: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations that are not possible with 225Ac. In this work, 225Ac- and 134Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging. METHODS: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody. RESULTS: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce's PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging. CONCLUSION: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.

11.
Artículo en Inglés | MEDLINE | ID: mdl-38987489

RESUMEN

PURPOSE: Immune cells are capable of eliminating leukemic cells, as evidenced by outcomes in hematopoietic cell transplantation (HCT). However, patients who fail induction therapy will not benefit from HCT due to their minimal residual disease (MRD) status. Thus, we aimed to develop an immunomodulatory agent to reduce MRD by activating immune effector cells in the presence of leukaemia cells via a novel fusion protein that chimerises two clinically tolerated biologics: a CD33 antibody and the IL15Ra/IL15 complex (CD33xIL15). METHODS: We generated a set of CD33xIL15 fusion protein constructs with varying configurations and identified those with the best in vitro AML-binding, T cell activation, and NK cell potentiation. Using 89Zr-immunoPET imaging we then evaluated the biodistribution and in vivo tumour retention of the most favourable CD33xIL15 constructs in an AML xenograft model. Ex vivo biodistribution studies were used to confirm the pharmacokinetics of the constructs. RESULTS: Two of the generated fusion proteins, CD33xIL15 (N72D) and CD33xIL15wt, demonstrated optimal in vitro behaviour and were further evaluated in vivo. These studies revealed that the CD33xIL15wt candidate was capable of being retained in the tumour for as long as its parental CD33 antibody, Lintuzumab (13.9 ± 3.1%ID/g vs 18.6 ± 1.1%ID/g at 120 h). CONCLUSION: This work demonstrates that CD33xIL15 fusion proteins are capable of targeting leukemic cells and stimulating local T cells in vitro and of concentrating in the tumour in AML xenografts. It also highlights the importance of 89Zr-immunoPET to guide the development and selection of tumour-targeted antibody-cytokine fusion proteins.

12.
J Hum Evol ; 186: 103466, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38134581

RESUMEN

Although the Turkana Basin is one of the driest regions of the East African Rift, its Plio-Pleistocene sediments are rich in freshwater vertebrates and invertebrates, providing evidence that freshwater resources were available to hominins in this region during the Plio-Pleistocene (4.2-0.7 Ma). Here we provide an overview of the hydroconnectivity of the Turkana Basin. We then review the period during which freshwater river and lake systems expanded into the western region of the Turkana Basin, where hominin and archeological sites have been discovered in sediments dating back to the Late Pliocene-Pleistocene. Freshwater conditions are reconstructed from river and lake sediments and the flora and micro- and macofauna they contain. Data synthesis suggests that drinking water and freshwater foods prevailed in the western region of the Turkana Basin at 4.20-3.98 Ma, 3.70-3.10 Ma, 2.53-2.22 Ma, then between 2.10 and 1.30 Ma and intermittently from 1.27 to 0.75 Ma. Milestones in hominin evolution occurred in this context, such as the first occurrence of Australopithecus anamensis (4.20-4.10 Ma) and Kenyanthropus platyops (3.50 Ma and 3.30-3.20 Ma), the presence of Paranthropus aethiopicus (2.53-2.45 Ma), early Homo (2.33 Ma), Paranthropus boisei (2.25 Ma and 1.77-1.72 Ma) and Homo ergaster/Homo erectus (1.75 Ma, 1.47-1.42 Ma and 1.10-0.90 Ma). Developments in hominin behavior also occurred during this timeframe, including the first known stone tools (3.30 Ma), the oldest Oldowan sites (2.34 Ma and 2.25 Ma) in the Turkana Basin, the earliest known evidence for the emergence of bifacial shaping in eastern Africa (1.80 Ma), and the first known Acheulean site (1.76 Ma). Our synthesis suggests that, diachronic variation in hydroconnectivity played a role on the amount of drinking water and freshwater foods available in the western region of the Turkana Basin, despite regional aridity.


Asunto(s)
Agua Potable , Hominidae , Animales , Kenia , Fósiles , Agua Dulce , Evolución Biológica
13.
J Hum Evol ; 194: 103579, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39173445

RESUMEN

A hominin mandible, KNM-ER 63000, and associated vertebrate remains were recovered in 2011 from Area 40 in East Turkana, Kenya. Tephrostratigraphic and magnetostratigraphic analyses indicate that these fossils date to ∼4.3 Ma. KNM-ER 63000 consists of articulating but worn and weathered mandibular corpora, with a broken right M2 crown and alveoli preserved at other tooth positions. Despite extensive damage, KNM-ER 63000 preserves diagnostic anatomy permitting attribution to Australopithecus anamensis. It can be distinguished from Australopithecus afarensis by its strongly inclined symphyseal axis with a basally convex, 'cut-away' external surface, a lateral corpus that sweeps inferomedially beneath the canine-premolar row, and alignment of the canine alveolus with the postcanine axis. KNM-ER 63000 is distinguished from Ardipithecus ramidus by its thick mandibular corpus and large M2 crown. The functional trait structure and enamel's stable carbon isotopic composition of the Area 40 large-mammal community suggests an environment comparable to Kanapoi and other ∼4.5-4 Ma eastern African sites that would have offered Au. anamensis access to both C3 and C4 food resources. With an age of ∼4.3 Ma, KNM-ER 63000 is the oldest known specimen of Au. anamensis, predating the Kanapoi and Asa Issie samples by at least ∼100 kyr. This specimen extends the known temporal range of Au. anamensis and places it in temporal overlap with fossils of Ar. ramidus from Gona, Ethiopia. The morphology of KNM-ER 63000 indicates that the reconfigured masticatory system differentiating basal hominins from the earliest australopiths existed in the narrow temporal window, if any, separating the two. The very close temporal juxtaposition of these significant morphological and adaptive differences implies that Ar. ramidus was a relative rather than a direct phyletic ancestor of earliest Australopithecus.


Asunto(s)
Fósiles , Hominidae , Mandíbula , Animales , Fósiles/anatomía & histología , Kenia , Hominidae/anatomía & histología , Mandíbula/anatomía & histología , Ambiente
14.
Ann Hepatol ; 29(1): 101164, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37802414

RESUMEN

INTRODUCTION AND OBJECTIVES: Congenital hepatic fibrosis (CHF) is a rare condition characterized by biliary tract changes and a geographic pattern of liver fibrosis. Liver biopsy is essential to confirm its diagnosis. The absence of specific clinical indicators in adults often leads to delays in diagnosis and management, while the natural history has not been well described. We sought to define the presentation and outcomes of adults with biopsy-proven CHF. MATERIALS AND METHODS: A retrospective chart review was conducted of patients diagnosed with CHF by liver biopsy. Continuous variables were summarized with the sample median and range. Categorical variables were summarized with number and percentage of patients. RESULTS: We identified 24 patients evaluated over a 20-year period, with a median age of 51 years (range 22-72 years) at initial presentation; 14 were male. The most common imaging findings were renal cysts (91.3%), splenomegaly (69.6%), and a cirrhotic-appearing liver (60.9%). The most commonly treated liver-related complications were cholangitis (45.8%), varices (45.8%), and hepatic encephalopathy (25%). Two patients died with a median length of follow-up of 2.9 years (range: 0.0-20.0 years). Two patients underwent transjugular intrahepatic portosystemic shunt (TIPS) placement to manage bleeding esophageal varices. Eight patients underwent liver transplantation (LT), the most common indication being decompensated disease (50%). CONCLUSIONS: CHF should be considered when patients present with cholangitis and/or complications of portal hypertension and have a cirrhotic appearing liver and renal cysts on imaging. Depending upon the disease severity, interventions such as TIPS or LT may be required.


Asunto(s)
Cirrosis Hepática , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Colangitis , Várices Esofágicas y Gástricas/diagnóstico , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/terapia , Hemorragia Gastrointestinal/etiología , Enfermedades Renales Quísticas/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Cirrosis Hepática/terapia , Estudios Retrospectivos
15.
J Am Chem Soc ; 145(26): 14276-14287, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37339504

RESUMEN

We report an innovative approach to producing bacteriochlorins (bacs) via formal cycloaddition by subjecting a porphyrin to a trimolecular reaction. Bacs are near-infrared probes with the intrinsic ability to serve in multimodal imaging. However, despite their ability to fluoresce and chelate metal ions, existing bacs have thus offered limited ability to label biomolecules for target specificity or have lacked chemical purity, limiting their use in bio-imaging. In this work, bacs allowed a precise and controlled appending of clickable linkers, lending the porphyrinoids substantially more chemical stability, clickability, and solubility, rendering them more suitable for preclinical investigation. Our bac probes enable the targeted use of biomolecules in fluorescence imaging and Cerenkov luminescence for guided intraoperative imaging. Bacs' capacity for chelation provides opportunities for use in non-invasive positron emission tomography/computed tomography. Herein, we report the labeling of bacs with Hs1a, a (NaV1.7)-sodium-channel-binding peptide derived from the Chinese tarantula Cyriopagopus schmidti to yield Bac-Hs1a and radiolabeled Hs1a, which shuttles our bac sensor(s) to mouse nerves. In vivo, the bac sensor allowed us to observe high signal-to-background ratios in the nerves of animals injected with fluorescent Bac-Hs1a and radiolabeled Hs1a in all imaging modes. This study demonstrates that Bac-Hs1a and [64Cu]Cu-Bac-Hs1a accumulate in peripheral nerves, providing contrast and utility in the preclinical space. For the chemistry and bio-imaging fields, this study represents an exciting starting point for the modular manipulation of bacs, their development and use as probes for diagnosis, and their deployment as formidable multiplex nerve-imaging agents for use in routine imaging experiments.


Asunto(s)
Porfirinas , Animales , Ratones
16.
Bioconjug Chem ; 34(11): 1925-1950, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37737084

RESUMEN

The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based in vivo pretargeting.


Asunto(s)
Azidas , Química Clic , Radioquímica , Azidas/química , Radiofármacos/química , Reacción de Cicloadición , Alquinos/química
17.
Inorg Chem ; 62(50): 20567-20581, 2023 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-36724083

RESUMEN

Three isotopes of scandium─43Sc, 44Sc, and 47Sc─have attracted increasing attention as potential candidates for use in imaging and therapy, respectively, as well as for possible theranostic use as an elementally matched pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO), an effective chelator for hard cations, as a potential ligand for use in radioscandium constructs with simple radiolabeling under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully characterized, both experimentally and theoretically. [47Sc]Sc-HOPO exhibited good stability in chemical and biological challenges over 7 days. In healthy mice, [43,47Sc]Sc-HOPO cleared the body rapidly with no signs of demetalation. HOPO is a strong candidate for use in radioscandium-based radiopharmaceuticals.


Asunto(s)
Piridonas , Radiofármacos , Animales , Ratones , Radiofármacos/química , Piridonas/química , Quelantes/química , Tomografía de Emisión de Positrones/métodos , Ligandos
18.
Proc Natl Acad Sci U S A ; 117(45): 28316-28327, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-33106429

RESUMEN

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.


Asunto(s)
Radioisótopos de Cobre/farmacología , Radioisótopos de Cobre/uso terapéutico , Medicina de Precisión/métodos , Radioinmunoterapia/métodos , Animales , Anticuerpos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Reacción de Cicloadición , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoconjugados , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones/métodos , Radioisótopos/farmacología , Radioisótopos/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Teach Learn Med ; : 1-11, 2023 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-38041804

RESUMEN

Phenomenon: Disrespectful behavior between physicians across departments can contribute to burnout, poor learning environments, and adverse patient outcomes. Approach: In this focus group study, we aimed to describe the nature and context of perceived disrespectful communication between emergency and internal medicine physicians (residents and faculty) at patient handoff. We used a constructivist approach and framework method of content analysis to conduct and analyze focus group data from 24 residents and 11 faculty members from May to December 2019 at a large academic medical center. Findings: We organized focus group results into four overarching categories related to disrespectful communication: characteristics and context (including specific phrasing that members from each department interpreted as disrespectful, effects of listener engagement/disengagement, and the tendency for communication that is not in-person to result in misunderstanding and conflict); differences across training levels (with disrespectful communication more likely when participants were at different training levels); the individual correspondent's tendency toward perceived rudeness; and negative/long-term impacts of disrespectful communication on the individual and environment (including avoidance and effects on patient care). Insights: In the context of predominantly positive descriptions of interdepartmental communication, participants described episodes of perceived disrespectful behavior that often had long-lasting, negative impacts on the quality of the learning environment and clinical work. We created a conceptual model illustrating the process and outcomes of these interactions. We make several recommendations to reduce disrespectful communication that can be applied throughout the hospital to potentially improve patient care, interdepartmental collaboration, and trainee and faculty quality of life.

20.
Eur J Nucl Med Mol Imaging ; 49(11): 3892-3897, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35441860

RESUMEN

PURPOSE: To verify the correlation between yttrium-90 glass microsphere radiation segmentectomy treatment intensification of hepatocellular carcinoma (HCC) and complete pathologic necrosis (CPN) at liver transplantation. METHODS: A retrospective, single center, analysis of patients with HCC who received radiation segmentectomy prior to liver transplantation from 2016 to 2021 was performed. The tumor treatment intensification cohort (n = 38) was prescribed radiation segmentectomy as per response recommendations identified in a previously published baseline cohort study (n = 37). Treatment intensification and baseline cohort treatment parameters were compared for rates of CPN. Both cohorts were then combined for an overall analysis of treatment parameter correlation with CPN. RESULTS: Sixty-three patients with a combined 75 tumors were analyzed. Specific activity, dose, and treatment activity were significantly higher in the treatment intensification cohort (all p < 0.01), while particles per cubic centimeter of treated liver were not. CPN was achieved in 76% (n = 29) of tumors in the treatment intensification cohort compared to 49% (n = 18) in the baseline cohort (p = 0.013). The combined cohort CPN rate was 63% (n = 47). ROC analysis showed that specific activity ≥ 327 Bq (AUC 0.75, p < 0.001), dose ≥ 446 Gy (AUC 0.69, p = 0.005), and treatment activity ≥ 2.55 Gbq (AUC 0.71, p = 0.002) were predictive of CPN. Multivariate logistic regression demonstrated that a specific activity ≥ 327 Bq was the sole independent predictor of CPN (p = 0.013). CONCLUSION: Radiation segmentectomy treatment intensification for patients with HCC prior to liver transplantation increases rates of CPN. While dose strongly correlated with pathologic response, specific activity was the most significant independent radiation segmentectomy treatment parameter associated with CPN.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Carcinoma Hepatocelular/patología , Estudios de Cohortes , Humanos , Neoplasias Hepáticas/patología , Necrosis/tratamiento farmacológico , Neumonectomía , Estudios Retrospectivos , Resultado del Tratamiento , Radioisótopos de Itrio/uso terapéutico
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