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1.
BMJ Glob Health ; 9(4)2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38589044

RESUMEN

National public health institutes (NPHIs) are crucial to the effectiveness of public health systems, including delivering essential public health functions and generating evidence for national health policies, strategies and plans. Currently, there is a significant lack of information regarding NPHI or NPHI-like organisations in Eastern Mediterranean Region (EMR) countries, including how they fit into their broader health systems governance landscape. NPHIs exist in 12 out of 22 EMR countries, yet there is no official International Association of National Public Health Institutes (IANPHI) regional network for the EMR, despite established IANPHI networks in four other regions. In 2022, the WHO's Eastern Mediterranean Regional Office led a study comprising an online survey and key informant interviews, which synthesised expert insights and summarised recommendations to strengthen the health systems governance-related role of NPHIs in EMR countries. Study participants included current and former high-level representatives of NPHIs, the government (eg, Ministries of Health, health regulatory authorities), multilateral organisations or non-governmental organisations focusing on health, and others identified as senior health systems governance experts from EMR. Insights and recommendations from experts varied widely, but there were also many common elements and overlaps. These included the need for enhancing NPHI functionalities and collaborative efforts with the public health sector (eg, Ministry of Health, Health Council) in health policy and decision-making formulation and implementation. This, in turn, requires advancing NPHI's fit-for-purpose and sustainable governance and financing arrangements, improving the accessibility and transparency of health data for NPHIs, strengthening engagement and collaboration between NPHIs and other health system actors (including the private sector), and promoting a more prominent role for NPHIs in the development and implementation of public health-related policies and legislation. While many excellent insights and thoughtful strategic guidance are provided, further adaptation may be needed to implement the proposed recommendations in different EMR country contexts going forward.


Asunto(s)
Política de Salud , Salud Pública , Humanos , Gobierno , Región Mediterránea , Programas de Gobierno
2.
Future Med Chem ; 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38634318

RESUMEN

Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50 = 0.0533 and 0.4195 µM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.

3.
Future Med Chem ; 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38639393

RESUMEN

Aim: Over the last few decades, therapeutic needs have led to a search for safer COX-2 inhibitors with potential anti-inflammatory and analgesic activity. Materials & methods: A new series of oxazolone and imidazolone derivatives 3a-c and 4a-r were synthesized and evaluated as anti-inflammatory and analgesic agents. COX-1/COX-2 isozyme selectivity testing and molecular docking were performed. Results: All compounds showed good activities comparable to those of the reference, celecoxib. The most active compounds 3a, 4a, 4c, 4e and 4f showed promising gastric tolerability with an ulcer index lower than that of celecoxib. The molecular docking of p-methoxyphenyl derivative 4c showed alkyl interaction with the side pocket His75 of COX-2 and achieved the best anti-inflammatory activity, with a COX-2 selectivity index better than that of celecoxib.

4.
bioRxiv ; 2024 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-38562769

RESUMEN

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

5.
PLoS One ; 19(4): e0302577, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38687741

RESUMEN

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural asymmetry of the spine and trunk affecting 2-4% of adolescents. Standard treatment is observation, bracing, and surgery for small, moderate, and large curves, respectively. Schroth exercises aim to correct posture and reduce curve progression. PURPOSE: This study aimed to determine the effect of Schroth exercises added to the standard care compared to standard care alone on torso asymmetry in AIS. METHODS: In a randomized controlled trial (NCT01610908), 124 participants with AIS (age: 10-18, Cobb: 10°-45°, Risser: ≤3) were randomly assigned to the control (Standard care only) or Schroth (Standard care + Schroth treatment) group. Schroth treatment consisted of 1-hour weekly supervised sessions and 30-45 minutes of daily home exercises for six months. The control group received Schroth exercises in the last six months of the 1-year monitoring period. Markerless 3D surface topography assessed torso asymmetry measured by maximum deviation (MaxDev) and root mean square (RMS). Intention to treat linear mixed effects model analysis was compared to the per protocol analysis. RESULTS: In the intention to treat analysis, the Schroth group (n = 63) had significantly larger decreased RMS (-1.2 mm, 95%CI [-1.5,-0.9]mm, p = 0.012) and MaxDev (-1.9mm, 95%CI [-2.4,-1.5]mm, p = 0.025) measurements compared to controls (n = 57) after six months of intervention. In the per protocol analysis (Schroth n = 39, control n = 36), the Schroth group also had a significantly larger decrease compared to the control in both the RMS (-1.0mm, 95%CI [-1.9, -0.2]mm, p = 0.013) and MaxDev measurements (-2.0mm, 95%CI [-3.3,-0.5]mm, p = 0.037). For the control group, both the intention to treat and per protocol analysis showed no difference in RMS and MaxDev in the last six months of Schroth intervention (p>0.5). CONCLUSION: Schroth Exercise treatment added to standard care (observation or bracing) reduced asymmetry measurements in AIS. As expected, a greater effect was observed for participants who followed the prescribed exercise treatment per protocol.


Asunto(s)
Terapia por Ejercicio , Postura , Escoliosis , Humanos , Escoliosis/terapia , Escoliosis/fisiopatología , Adolescente , Femenino , Masculino , Terapia por Ejercicio/métodos , Niño , Resultado del Tratamiento , Modalidades de Fisioterapia
6.
PLoS One ; 19(2): e0294311, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38319945

RESUMEN

The in-vitro anti-proliferative evaluation of Sinularia levi total extract against three cell lines revealed its potent effect against Caco-2 cell line with IC50 3.3 µg/mL, followed by MCF-7 and HepG-2 with IC50 6.4 µg/mL and 8.5 µg/mL, respectively, in comparison to doxorubicin. Metabolic profiling of S. levi total extract using liquid chromatography coupled with high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) revealed the presence of phytoconstituents clusters consisting mainly of steroids and terpenoids (1-20), together with five metabolites 21-25, which were additionally isolated and identified through the phytochemical investigation of S. levi total extract through various chromatographic and spectroscopic techniques. The isolated metabolites included one sesquiterpene, two steroids and two diterpenes, among which compounds prostantherol (21) and 12-hydroperoxylsarcoph-10-ene (25) were reported for the first time in Sinularia genus. The cytotoxic potential evaluation of the isolated compounds revealed variable cytotoxic effects against the three tested cell lines. Compound 25 was the most potent with IC50 value of 2.13 ± 0.09, 3.54 ± 0.07 and 5.67 ± 0.08 µg/mL against HepG-2, MCF-7 and Caco-2, respectively, followed by gorgosterol (23) and sarcophine (24). Additionally, network analysis showed that cyclin-dependent kinase 1 (CDK1) was encountered in the mechanism of action of the three cancer types. Molecular docking analysis revealed that CDK1 inhibition could possibly be the reason for the cytotoxic potential.


Asunto(s)
Antineoplásicos , Farmacología en Red , Humanos , Células CACO-2 , Simulación del Acoplamiento Molecular , Antineoplásicos/farmacología , Extractos Vegetales/farmacología , Esteroides
7.
Future Med Chem ; 16(4): 311-334, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38293746

RESUMEN

Background: Dual COX/5-LOX inhibition is a bright strategy for developing new potent and safe anti-inflammatory agents. Methods: New imines were synthesized and evaluated for their anti-inflammatory activity. The most active compounds were further investigated for their safety profile. Their molecular docking and physicochemical parameters were assessed. A new LC-MS/MS method was developed for the quantification of compound 4d in rat plasma. Results: Synthesized compounds were found to have anti-inflammatory activity (77-88% edema inhibition). In addition, 4d, 5m and 7d showed analgesic activity (92.50, 95.71 and 96.28% protection, respectively). 4d showed dual COX-2/5-LOX activity. Molecular docking expected the binding pattern of compounds in COX-1, COX-2 and 5-LOX active sites. The in vivo pharmacokinetic parameters of compound 4d were also obtained.


Asunto(s)
Antiinflamatorios , Espectrometría de Masas en Tándem , Ratas , Animales , Ciclooxigenasa 2/metabolismo , Simulación del Acoplamiento Molecular , Cromatografía Liquida , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Edema/inducido químicamente , Edema/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/farmacología , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Ciclooxigenasa 2/química , Relación Estructura-Actividad , Antiinflamatorios no Esteroideos/química , Estructura Molecular
8.
Clin Respir J ; 18(1): e13721, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38286743

RESUMEN

INTRODUCTION: Bronchoalveolar lavage (BAL) is frequently used in pulmonary medicine though it requires further optimization. Practical obstacles such as patient safety and procedural limitation have to date precluded large, controlled trials aimed at standardization of BAL procedure. Indeed, BAL guidelines are based on observational data. Innovative research methods are necessary to advance the clinical practice of BAL. METHODS: In our study, we evaluated the effect of injecting a gelatinized barium solution into different lobes and segments of cadaveric lungs. As the technique requires an irreversible injection into lung airspaces, it is not suitable for in vivo purposes. We measured the volume returned from BAL as well as the distribution of BAL injection via dissection. Segmental anatomic orientation was compared to a radiologist's impression of plain film radiographs taken of injected lungs. RESULTS: Mean injected volume distributions were greatest in the upper lobes and lowest in the lower lobes; mean ratios of injected volume distribution to lung lobe volume also followed this trend. Cannulated bronchi orders favored lower branches in the upper lobe and higher branches in the lower lobes. Segmental anatomy varied by the lung lobe injected and was most varied in the lower lobes. CONCLUSION: This novel gelatinized-barium injection technique provides a minimally complex method to yield clinically meaningful feedback on the performance of BAL. The technique is also adaptable to study of procedural parameters in the context of variable lung anatomies and pathologies.


Asunto(s)
Sulfato de Bario , Pulmón , Humanos , Bario , Lavado Broncoalveolar , Pulmón/diagnóstico por imagen , Bronquios , Líquido del Lavado Bronquioalveolar , Broncoscopía/métodos
9.
Sci Rep ; 14(1): 2546, 2024 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-38291122

RESUMEN

The crude extract of Hemimycale sp. marine sponge was evaluated as a cytotoxic drug against different cell lines; whereas it exhibited promising selective activity toward the breast cancer cell line only with IC50 value 199.6 ± 0.00512 µg/ml. Moreover, its cytotoxic activity against the breast cancer cell line was reevaluated upon forming total extract-loaded niosomes. This revealed an IC50 value of 44.35 ± 0.011128 µg/ml, indicating the potential contribution of niosomes in boosting cell penetration and activity as a result. Owing to highlight the bioactive constituents responsible for the cytotoxic activity, metabolomics profiling of Hemimycale sp. was performed using liquid chromatography coupled with high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) revealing tentative identification of phytoconstituents clusters like as, diterpenes, sesterterpenes and sterols. Additionally, the cytotoxic activity of the crude extract was explained on the molecular level, whereas the dereplicated compounds were evaluated in silico against the Epidermal Growth Factor Receptor tyrosine kinase (EGFR). The sesterterpenoid derivatives phorbaketal A acetate (12) and secoepoxy ansellone A (13) together with mycalol-522 (17) showed the best binding energy.


Asunto(s)
Antineoplásicos , Poríferos , Animales , Liposomas , Espectrometría de Masa por Ionización de Electrospray , Antineoplásicos/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/química
10.
J Trop Med ; 2023: 2289552, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38075586

RESUMEN

Objective: Malaria during pregnancy is a priority area for malaria research and control as pregnant women represent a high risk group for severe malaria, and the presentation of malaria during pregnancy varies according to the level of transmission in the area; so the aim of this study is to determine the prevalence rates of malaria parasite among pregnant women attending to Saudi Kassala Teaching hospital in Kassala state, 2022. Methods: A cross-sectional study was carried out in Saudi Kassala Teaching hospital in Kassala State. This study involved one hundred and eighty-five blood samples collected from pregnant women who was then examined by using blood films and ICT for malaria, and the data were collected by a structured questionnaire and analyzed using SPSS version 21. Results: The prevalence of malaria among pregnant women was 2.2% (95% CI: 0.006-0.054). There was no significant difference among the different age groups with respect to the prevalence of malaria (P value = 0.483). The prevalence of malaria in rural residency was 2.2%, and this was significantly more common than the urban residency (P value = 0.021). When compared across the gestational trimesters, there was no significant difference between them (P value = 0.518). The number of gravidity is not related to malaria infection (P value = 0.737). The presence of symptom compliant of malaria during pregnancy does not suggest the presence of malaria (P value = 0.152). No difference was found between the different educational levels with respect to the prevalence of malaria (P value = 0.362). The result showed that there was 1 (0.5%) negative result in ICT which was positive in blood film for malaria (BFFM) and there were 3 (1.6%) positive malaria parasites by both methods in all 185 samples with statistically insignificant differences (P = 0.703). Conclusion: Plasmodium falciparum was only species detected in this study. Malaria among pregnant women was more prevalent in rural areas. However, other factors such as age, gestational age, gravidity, and educational level do not affect the prevalence of malaria in pregnant women. The presence of symptomatic compliant of malaria during pregnancy does not suggest the presence of malaria. The use of ICT or BFFM has similar diagnostic outcome for malaria in pregnancy.

11.
BMC Microbiol ; 23(1): 308, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37884900

RESUMEN

BACKGROUND: Cancer continues to be one of the biggest causes of death that affects human health. Chemical resistance is still a problem in conventional cancer treatments. Fortunately, numerous natural compounds originating from different microbes, including fungi, possess cytotoxic characteristics that are now well known. This study aims to investigate the anticancer prospects of five fungal strains that were cultivated and isolated from the Red Sea soft coral Paralemnalia thyrsoides. The in vitro cytotoxic potential of the ethyl acetate extracts of the different five isolates were evaluated using MTS assay against four cancer cell lines; A549, CT-26, MDA-MB-231, and U87. Metabolomics profiling of the different extracts using LC-HR-ESI-MS, besides molecular docking studies for the dereplicated compounds were performed to unveil the chemical profile and the cytotoxic mechanism of the soft coral associated fungi. RESULTS: The five isolated fungal strains were identified as Penicillium griseofulvum (RD1), Cladosporium sphaerospermum (RD2), Cladosporium liminiforme (RD3), Penicillium chrysogenum (RD4), and Epicoccum nigrum (RD5). The in vitro study showed that the ethyl acetate extract of RD4 exhibited the strongest cytotoxic potency against three cancer cell lines A549, CT-26 and MDA-MB-231 with IC50 values of 1.45 ± 8.54, 1.58 ± 6.55 and 1.39 ± 2.0 µg/mL, respectively, also, RD3 revealed selective cytotoxic potency against A549 with IC50 value of 6.99 ± 3.47 µg/mL. Docking study of 32 compounds dereplicated from the metabolomics profiling demonstrated a promising binding conformation with EGFR tyrosine kinase that resembled its co-crystallized ligand albeit with better binding energy score. CONCLUSION: Our results highlight the importance of soft coral-associated fungi as a promising source for anticancer metabolites for future drug discovery.


Asunto(s)
Antozoos , Antineoplásicos , Humanos , Animales , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Filogenia , Antineoplásicos/farmacología , Hongos/metabolismo
12.
RSC Adv ; 13(34): 24003-24022, 2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37577088

RESUMEN

A novel series of 2,4,5- and 2,3,4-trisubstituted thiazole hybrids with 1,3,4-thiadiazolylbenzenesulfonamide was designed following the tail approach as possible hCAIX inhibitors. The key intermediate 1 was condensed with thiosemicarbazide 2a to give 1,3,4-thiadiazolylthiosemicarbazone 3, which upon hetero-cyclization with substituted α-haloketones and esters afforded 2,4,5-trisubstituted thiazole-1,3,4-thiadiazole conjugates 4-8. Furthermore, the trisubstituted thiazole-1,3,4-thiadiazole hybrids 12a-d were synthesized via the regioselective cyclization of 4-substituted-1,3,4-thiadiazolylthiosemicarbazones with phenacyl bromide. The cyclized 2,4-disubstituted thiazole 4 enhanced cytotoxicity by nine, four and two times against HepG-2, Caco2, and MCF-7, respectively. Moreover, the simple methyl substitution on the thiosemicarbazone terminus 9a improved the parent derivative 3 cytotoxicity by nine, fourteen, and six times against HepG-2, Caco2, and MCF-7, respectively. This astonishing cytotoxicity was elaborated with hCAIX molecular docking simulation of 4, 9a, and 12d demonstrating binding to zinc and its catalytic His94. Furthermore, molecular dynamic simulation 9a revealed stable hydrogen bonding with hCAIX with interaction energy of -61.07 kcal mol-1 and ΔGbinding MM-PBSA of -9.6 kcal mol-1.

13.
Cureus ; 15(7): e42453, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37637554

RESUMEN

Rat-bite fever (RBF) is a rare systemic infectious disease caused by Streptobacillus moniliformis, Spirillum minus, or Streptobacillus notomytis. As the name implies, the disease is typically transmitted by a rat bite. RBF usually presents as a combination of fever, arthritis, and rash. Definitive diagnosis of RBF may prove difficult, as the responsible bacteria are not easily identified with standard testing. We describe a case of RBF in a 34-year-old female who presented with fever, chills, polyarthralgia, and skin rash following a rat bite. Initial vital signs were remarkable for fever and tachycardia. Physical examination revealed an erythematous vesicular and papular rash involving her extremities, buttocks, and oral mucosa. Blood cultures were negative. A skin biopsy revealed leukocytoclastic vasculitis and was negative for Gram stain. Further analysis using specialized immunohistochemistry and polymerase chain reaction (PCR) identified S. moniliformis. A diagnosis of RBF was made, and the patient was successfully treated with a two-week course of doxycycline.

14.
Dermatol Online J ; 29(3)2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37591268

RESUMEN

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma that affects sun-damaged skin. Histologically, the tumor consists of round cells with fine chromatin positive for cytokeratin 20 in ~90% of cases. Rare cases of MCC can regress spontaneously and present as nodal metastasis. Nodal MCC of unknown primary can cause a potential pitfall as they can be misinterpreted as other neuroendocrine carcinomas such as small cell carcinoma. We report a case of nodal MCC with an atypical immunohistochemistry pattern presented as bilateral axillary lymphadenopathy in a 90-year-old man with a remote history of a skin lesion that healed spontaneously leaving a scar.


Asunto(s)
Carcinoma de Células de Merkel , Carcinoma Neuroendocrino , Neoplasias Cutáneas , Masculino , Humanos , Anciano de 80 o más Años , Carcinoma de Células de Merkel/diagnóstico , Queratina-20 , Cicatriz
15.
Helicobacter ; 28(5): e13004, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37391943

RESUMEN

Nano-structure Cu(II) complex [Cu(AMAB)2 ]Cl2 with Schiff base (AMAB) derived from the condensation between 4-(dimethylamino)benzaldehyde and amoxicillin trihydrate was prepared. (AMAB) Schiff base and its Cu(II) complex were identified and confirmed by different physicochemical techniques. The Schiff base (AMAB) was coordinated to copper ion through carbonyl oxygen and imine nitrogen donor sites. X-ray powder diffraction shows a cubic crystal system of the Cu(II) complex. The density functional theory was used to optimize the structure geometries of the investigated compounds. The molecular docking of the active amino acids of the investigated proteins' interactions with the tested compounds was evaluated. The bactericidal or bacteriostatic effect of the compounds was screened against some bacterial strains. The activity of Cu-chelate against Gram-negative bacteria was mainly more effective than its (AMAB) ligand and vice versa in the case of Gram-positive bacteria. The biological activity of the prepared compounds with biomolecules calf thymus DNA (CT-DNA) was determined by electronic absorption spectra and DNA gel electrophoresis technique. All studies revealed that the Cu-chelate derivative exhibited better binding affinity to both CT-DNA than the AMAB and amoxicillin itself. The anti-inflammatory effect of the designed compounds was determined by testing their protein denaturation inhibitory activity spectrophotometrically. All obtained data supported that the designed nano-Cu(II) complex with Schiff base (AMAB) is a potent bactericide against H. pylori, and exhibits anti-inflammatory activity. The dual inhibition effects of the designed compound represent a modern therapeutic approach with extended spectrum of action. Therefore, it can act as good drug target in antimicrobial and anti-inflammtory therapies. Finally, H. pylori resistance to amoxicillin is absent or rare in many countries, thus amoxicillin nanoparticles may be beneficial for countries where amoxicillin resistance is reported.


Asunto(s)
Antiinfecciosos , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Helicobacter pylori/metabolismo , Bases de Schiff/farmacología , Bases de Schiff/química , Cobre/farmacología , Cobre/química , Amoxicilina/farmacología , Simulación del Acoplamiento Molecular , Infecciones por Helicobacter/tratamiento farmacológico , Antiinfecciosos/farmacología , Antibacterianos/farmacología , Antibacterianos/química , ADN/química , ADN/metabolismo , Pruebas de Sensibilidad Microbiana
16.
Cancer Res Commun ; 3(7): 1366-1377, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37501682

RESUMEN

NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader, together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER+ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER+ patient-derived xenograft (PDX) models by DNA and mRNA sequencing and found that more than half of these models carried an NF1 shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pulldown. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An IHC assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER+ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis. Significance: A major challenge for targeting the consequence of tumor suppressor disruption is the accurate assessment of protein functional inactivation. NF1 can repress both RAS and ER signaling, and a ComboMATCH trial is underway to treat the patients with binimetinib and fulvestrant. Herein we report a MS-verified NF1 IHC assay that can determine a threshold for NF1 loss to predict treatment response. These approaches may be used to identify and expand the eligible patient population.


Asunto(s)
Neoplasias de la Mama , Proteogenómica , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neurofibromina 1/genética , Fulvestrant/farmacología , Receptores de Estrógenos/genética , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción NFI , ARN Mensajero , Quinasas de Proteína Quinasa Activadas por Mitógenos
17.
Cureus ; 15(6): e40011, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37425545

RESUMEN

Extranodal natural killer/T-cell lymphoma (ENKTL) is a subtype of non-Hodgkin's lymphoma, and it is exceedingly rare in North America. The "extranasal" subtype of ENKTL frequently involves the skin and typically has an aggressive course with no current standard of treatment available. In this report, we present a case of cutaneous ENKTL in an otherwise healthy middle-aged male.

18.
Respir Med Case Rep ; 44: 101874, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37260562

RESUMEN

Black pleural effusions (BPE) are rare, exudative pleural effusions that produce a black fluid on thoracentesis. While the name and definition of this pathology is undeniably simple, the etiologies, outcomes, and treatments for BPE are incredibly complex. Currently, BPE is not well-demonstrated in the literature. This case series reports three patients with different etiologies, past medical histories, presenting symptoms, treatments, and outcomes. BPE caused by pancreatic-pleural fistula and opportunistic infections are demonstrated in this case series. This report shows that early identification and treatment of the underlying cause of BPE is critical to the recovery of the patients.

19.
J Cutan Pathol ; 50(8): 723-729, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37127848

RESUMEN

Extragastrointestinal stromal tumors (EGISTs) carry the same morphological, immunohistochemical and molecular features as gastrointestinal stromal tumors (GISTs) and involve extragastrointestinal tract soft tissue. The majority of reported EGIST cases arise from intraabdominal, retroperitoneal, or pelvic soft tissue. A significant subset of such tumors originates from the gastrointestinal muscle layer, grows in an exophytic manner, then loses attachment to the gastrointestinal tract. Consequently, true EGISTs are exceedingly rare. Herein, we are reporting a case of a vulvar EGIST. A 77-year-old woman presented with a painless subcutaneous nodule on the right perineum. An excisional biopsy showed a fairly circumscribed bland spindle cell lesion in the dermis. The tumor cells were positive for CD117 and ANO1/DOG-1 and negative for smooth muscle myosin, smooth muscle actin, STAT6, low- and high-molecular-weight cytokeratins, SOX10, MART-1, CD10, S-100 protein, and estrogen and progesterone receptors. A diagnosis of EGIST was made and complete excision was recommended. Superficial/subcutaneous EGISTs are extremely rare, and it is important for dermatopathologists to be aware of this entity as it can be misdiagnosed as more common spindle cell neoplasms, both benign and malignant, including but not limited to smooth muscle neoplasms (leiomyoma/leiomyosarcoma), spindle cell melanoma, and sarcomatoid squamous cell carcinoma.


Asunto(s)
Tumores del Estroma Gastrointestinal , Leiomiosarcoma , Humanos , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/patología , Inmunohistoquímica , Proteínas Proto-Oncogénicas c-kit
20.
BMC Med Educ ; 23(1): 274, 2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37085853

RESUMEN

BACKGROUND: Despite its importance, teaching at the bedside is declining over time. This purported decline has not been quantified. Quantifying bedside teaching is challenging, and we found only one study quantifying bedside teaching on a hospitalist service. OBJECTIVE: We conducted a study to understand the prevalence of bedside teaching in our medical intensive care unit. METHODS: We conducted a single-center single-unit study in the medical intensive care unit of an academic tertiary care institution. We used a survey tool to assess perceived time spent on bedside teaching, quality of teaching, and total rounding time. In parallel, independent observers objectively measured time spent on rounds and on bedside teaching. Residents were asked to complete the survey once a week. Independent observers collected data daily and weekly averages were obtained. RESULTS: 43 responses were collected over a 4-month period. Most respondents (73%) reported a total rounding time of either 90-120 min or greater than 120 min. Median reported bedside teaching time was 16-20 min with 16 respondents (37%) reporting less than 15 min and 27 respondents (63%) reporting 16 min or more. The amount of time spent on bedside teaching was reported as adequate or more than adequate by 77% (33) of respondents with 58% (25) reporting that bedside teaching was very or extremely effective in helping them learn. Mean census reported by the independent observers was 12.75 patients per team. Bedside teaching represented an average of 12% of total rounding time, 16.85 min per day. While total rounding time increased with increasing census, there was no decline in bedside teaching time. CONCLUSION: It is reported that bedside teaching has decreased over time. Our study has demonstrated that bedside teaching occurs in our Medical ICU, and though it represents a minority of the time spent on rounds, residents still reported teaching in the ICU to be adequate.


Asunto(s)
Rondas de Enseñanza , Humanos , Unidades de Cuidados Intensivos , Factores de Tiempo , Percepción
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