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1.
Cureus ; 16(8): e67691, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39318899

ABSTRACT

Primary tracheal tumors are rare, with adenoid cystic carcinoma (ACC) of the trachea being the second most common malignancy of the trachea. Radical surgical resection is found to have better survival outcomes in tracheal ACC. However, with higher submucosal spread rates in tracheal ACC and the inability to achieve clear margins, complete resection is not usually achievable. In these cases, the use of a 60-70 Gy radiation dose is deemed to be sufficient for definitive treatment with or without concurrent chemotherapy. We report a case of an unresectable ACC treated with online daily adaptive cone beam computed tomography (CBCT) radiotherapy on Ethos™ (Varian Medical Systems, Palo Alto, CA). She was planned to receive 59.4 Gy in 33 fractions in two phases. For daily treatment delivery, the patient was set up on the couch using the surface-guided radiotherapy (SGRT) system of AlignRT™ (Vision RT Ltd., London, UK) and translated to the treatment isocenter. A CBCT scan was acquired, followed by rigid registration with the planning scan and PET CT. Organs at risk (OAR) and primary targets were auto-generated by the AI in a two-step process, reviewed, and edited by the radiation oncologist. Adapted and scheduled plans were compared regarding planning target volume (PTV) coverage and dose to OAR. Better PTV coverage was seen in 26 of 33 fractions with the adapted plan. On the days with lesser coverage, adapted plans demonstrated improvement in the hotspot reduction and reduction in hard dose constraints of the esophagus and lungs. Hence, adapted plans were selected for all treatment days. Our results highlight the superior target coverage and improved OAR-sparing plans in daily online adaptive radiotherapy (o-ART) compared to image-guided radiotherapy (IGRT) plans. The system's ability to adapt to daily anatomical changes, improved target coverage, and better sparing of OARs make it an encouraging option for malignancies requiring motion management.

2.
Int Psychogeriatr ; : 1-13, 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39297292

ABSTRACT

OBJECTIVES: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales. DESIGN: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores. SETTING: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively. PARTICIPANTS: Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease. MEASUREMENTS: The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory - Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics. RESULTS: Among the MCID was a decrease of four points (95% CI: -4.0 to -4.8) on the NPI-A, 0.56 points (95% CI: -0.47 to -0.65) on the DAIR, and three points on the AES-I (95% CI: -0.9 to -5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID. CONCLUSIONS: MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales.

3.
Front Artif Intell ; 7: 1438012, 2024.
Article in English | MEDLINE | ID: mdl-39118788

ABSTRACT

Introduction: AI technologies have the potential to transform patient care. AI has been used to aid in differential diagnosis and treatment planning for psychiatric disorders, administer therapeutic protocols, assist with interpretation of cognitive testing, and patient treatment planning. Despite advancements, AI has notable limitations and remains understudied and further research on its strengths and limitations in patient care is required. This study explored the responses of AI (Chat-GPT 3.5) and trained clinicians to commonly asked patient questions. Methods: Three clinicians and AI provided responses to five dementia/geriatric healthcare-related questions. Responses were analyzed by a fourth, blinded clinician for clarity, accuracy, relevance, depth, and ease of understanding and to determine which response was AI generated. Results: AI responses were rated highest in ease of understanding and depth across all responses and tied for first for clarity, accuracy, and relevance. The rating for AI generated responses was 4.6/5 (SD = 0.26); the clinician s' responses were 4.3 (SD = 0.67), 4.2 (SD = 0.52), and 3.9 (SD = 0.59), respectively. The AI generated answers were identified in 4/5 instances. Conclusions: AI responses were rated more highly and consistently on each question individually and overall than clinician answers demonstrating that AI could produce good responses to potential patient questions. However, AI responses were easily distinguishable from those of clinicians. Although AI has the potential to positively impact healthcare, concerns are raised regarding difficulties discerning AI from human generated material, the increased potential for proliferation of misinformation, data security concerns, and more.

4.
Ann Card Anaesth ; 27(3): 270-273, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38963367

ABSTRACT

ABSTRACT: Isolated persistent left superior vena cava (PLSVC) is a very rare congenital thoracic venous system anomaly and is commonly an incidental finding, usually detected during central venous access, cardiac catheterization, or cardiothoracic surgeries. This is a rare case report wherein the patient is a known case of ischemic heart disease with s/p percutaneous transluminal coronary angioplasty (PTCA) with a stent to left anterior descending (LAD) artery with in-stent re-stenosis presented with complete heart block and had an unanticipated discovery of isolated PLSVC on facing difficulty during the transvenous approach of permanent pacemaker implantation (PPI). In this case report, we inspect the challenges associated with and various clinical implications of isolated PLSVC.


Subject(s)
Heart Block , Myocardial Ischemia , Persistent Left Superior Vena Cava , Stents , Humans , Myocardial Ischemia/surgery , Heart Block/therapy , Persistent Left Superior Vena Cava/complications , Male , Angioplasty, Balloon, Coronary/methods , Vena Cava, Superior/abnormalities , Vena Cava, Superior/diagnostic imaging , Middle Aged
5.
Int J Biol Macromol ; 275(Pt 1): 133586, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38960242

ABSTRACT

In the face of agricultural challenges posed by both abiotic and biotic stressors, phytopathogens emerge as formidable threats to crop productivity. Conventional methods, involving the use of pesticides and microbes, often lead to unintended consequences. In addressing this issue, ICAR -Indian Institute of Oilseeds Research (ICAR-IIOR) has developed a chitosan-based double-layer seed coating. Emphasizing crop input compatibility, entrapment, and characterization, the study has yielded promising results. The double-layer coating on groundnut seeds enhanced germination and seedling vigor. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) confirmed the structural changes and entrapment of crop inputs. The persistence of T. harzianum (Th4d) and Bradyrhizobium sp. in chitosan blended film in studied soils revealed that viable propogules of Th4d were recorded in double layer treatment combination with 3.54 and 3.50 Log CFUs/g of soil (colony forming units) and Bradyrhizobium sp. with 5.34 and 5.27 Log CFUs/g of soil at 90 days after application (DAA). Root colonization efficacy studies of Th4d and Bradyrhizobium sp. in groundnut crop in studied soils revealed that, maximum viable colonies were observed at 45 days after sowing (DAS). This comprehensive study highlights the potential of chitosan-based double-layer seed coating providing a promising and sustainable strategy for stress management in agriculture.


Subject(s)
Bradyrhizobium , Chitosan , Seeds , Stress, Physiological , Chitosan/chemistry , Chitosan/pharmacology , Seeds/drug effects , Bradyrhizobium/drug effects , Bradyrhizobium/physiology , Stress, Physiological/drug effects , Germination/drug effects , Seedlings/drug effects , Seedlings/growth & development , Vigna/drug effects , Vigna/growth & development
6.
Eur Urol Focus ; 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38866663

ABSTRACT

BACKGROUND AND OBJECTIVE: The introduction of the single-port (SP) robotic system has led to new approaches in robot-assisted radical prostatectomy (RARP), such as the transvesical (TV) approach, offering high rates of early urinary continence. While previous studies of SP TV RARP have identified perioperative factors influencing continence outcomes, the impact of anatomical factors remains unexplored. This study aims to assess magnetic resonance imaging (MRI)-based anatomical predictors of urinary continence after SP TV RARP. METHODS: A retrospective analysis of consecutive SP TV RARP cases (November 2020 to June 2023) with preoperative prostate MRI was performed. Two urogenital radiologists independently evaluated ten anatomical parameters to distinguish patients achieving urinary continence within 1 wk and 3 mo. Nonparametric methods estimated receiver operating characteristic curves (area under the curve [AUC]) and inter-reader agreement. KEY FINDINGS AND LIMITATIONS: In 120 cases, 40% achieved continence within 1 wk, rising to 71.7% by 3 mo. Membranous urethra length (MUL) alone was significantly associated with continence at 3 mo (AUC: 0.67, p = 0.003). At 1 wk, several parameters, including anteroposterior diameter of the prostate, coronal membranous urethra length, prostate volume, and transverse diameter of the prostate, showed promise in predicting continence. CONCLUSIONS AND CLINICAL IMPLICATIONS: A longer preoperative MUL was significantly associated with better odds of an early return to urinary continence after SP TV RARP. Each 1-mm increase in coronal MUL was associated with a 27% increase in the odds of continence at 3 mo. This information can aid in patient counseling and expectations preoperatively. PATIENT SUMMARY: Urinary incontinence is a common outcome after prostate cancer surgery, particularly in the early months. Recently, the single-port (SP) robotic system has emerged, localizing surgery to the diseased area. With the SP robot, accessing the prostate via the bladder leads to high rates of early continence. Our study reveals that the longer the urethral portion beneath the prostate, the higher the likelihood of regaining continence within 3 mo after surgery.

7.
Cureus ; 16(5): e60895, 2024 May.
Article in English | MEDLINE | ID: mdl-38836152

ABSTRACT

Background Of late, the interest in accelerated treatment protocols in repetitive transcranial magnetic stimulation (TMS) for the treatment of depression and obsessive-compulsive disorder (OCD) has been gaining momentum. Studies have already found that the patterned theta burst stimulation is non-inferior to the standard high-frequency stimulation in treating depression. The objective of the present study was to evaluate the clinical efficacy of a customized accelerated combination TMS naturalistic setting. Methods Retrospective analysis of pre and post-deep repetitive TMS responses in depression and OCD patients was performed. About 391 Depression and 239 OCD patients' data was analyzed. Customized treatment protocols consisted of twice daily high-frequency stimulations intervened by one theta burst stimulation. The outcome measures were a day six score in depression and a day 10 score in OCD, compared to day one baseline scores. Results The overall response rate in depression was 60.86%, estimated as a >50% reduction in the Hamilton Depression Rating Scale (HAM-D) 21 items score, and 62.76% in OCD, estimated as a >35% reduction in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score. The mean reduction of YBOCS and HAM-D was statistically significant at p<0.0001 (Mann-Whitney U test statistic=9442.5, z=12.66 for YBOCS and 16673.5, z=18.92 for HAM-D). Corresponding effect size estimations revealed Cohen's d value of 1.40 and 1.59, respectively. Conclusions The response rates achieved at day six and day 10 in depression and OCD, respectively, were comparable to previous studies employing standard treatment protocols. The accelerated protocol produced satisfactory short-term clinical outcomes that were effective in the early management of the illness without any serious adverse effects.

9.
Int J Geriatr Psychiatry ; 39(6): e6108, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38858522

ABSTRACT

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.


Subject(s)
Accidental Falls , Alzheimer Disease , Apathy , Central Nervous System Stimulants , Methylphenidate , Weight Loss , Humans , Alzheimer Disease/drug therapy , Methylphenidate/therapeutic use , Methylphenidate/adverse effects , Female , Male , Apathy/drug effects , Aged , Central Nervous System Stimulants/therapeutic use , Central Nervous System Stimulants/adverse effects , Aged, 80 and over , Weight Loss/drug effects , Accidental Falls/statistics & numerical data , Double-Blind Method , Sleep Initiation and Maintenance Disorders/chemically induced , Sleep Initiation and Maintenance Disorders/drug therapy
10.
Diagn Microbiol Infect Dis ; 109(3): 116306, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38735146

ABSTRACT

Rapid identification of microbial pathogens "directly" from positive blood cultures (PBCs) is critical for prompt initiation of empirical antibiotic therapy and clinical outcomes. Towards higher microbial identification rates, we modified a published initial serum separator tubes-based MALDI-TOF-MS protocol, for blood culture specimens received at a non-hospital based standalone diagnostic laboratory, Bangalore, India: (a) "Initial" protocol #1: From 28 PBCs, identification= 39% (Gram-negative= 43%: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa; Gram-positive: 36%: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus haemolyticus); mis-identification= 14%; non-identification= 47%. (b) "Modified" protocol #2: Quality controls (ATCC colonies spiked in negative blood cultures) From 7 analysis, identification= 100% (Escherichia coli, Klebsiella pneumonia, Klebsiella oxytoca, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus); From 7 PBCs, identification= 57%; mis-identification= 14%; non-identification= 29%. Microbial preparations of highest quality and quantity for proteomic analysis and separate spectra matching reference databases for colonies and PBCs are needed for best clinical utility.


Subject(s)
Blood Culture , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Humans , Blood Culture/methods , India , Bacteria/isolation & purification , Bacteria/classification , Bacteremia/diagnosis , Bacteremia/microbiology
11.
ACS Pharmacol Transl Sci ; 7(5): 1302-1309, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38751629

ABSTRACT

The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic. About 80% of cancer deaths are due to metastases, and yet targeted therapies for metastatic cancers are scarce. We discovered a small molecule, BFC1103, which changes the conformation of Bcl-2 to convert the antiapoptotic protein to a proapoptotic protein. BFC1103-induced apoptosis is dependent on the expression levels of Bcl-2, with higher levels causing more apoptosis. BFC1103 suppressed the growth of breast cancer lung metastasis. BFC1103 has the potential for further optimization and development for clinical testing in metastatic cancers that express Bcl-2. This study demonstrates a new approach to target Bcl-2 using a small molecule, BFC1103, to suppress metastatic disease.

12.
Org Biomol Chem ; 22(19): 3876-3881, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38651749

ABSTRACT

Predicting selectivity and conversion in a confined reaction medium under photochemical conditions is highly challenging as compared to the corresponding conventional synthesis. Herein, we report the use of a simple carbohydrate-derived eutectogel to facilitate LED-light-induced regioselective synthesis of 4-arylamino-1,2-naphthoquinones in good yield. This methodology, by including a reusable reaction medium, proved to have the potential of affording the regioselective formation of various desired products in good yields.

13.
Cureus ; 16(3): e55684, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38586691

ABSTRACT

Background "Awe" is typically an inspiring emotional response to perceptually vast stimuli signifying the transcendence beyond all cognitive frames of reference when we encounter the unexpected. Physicians' experience of awe in clinical care interactions has not been studied in an empirical, evidence-based way. We aim to present a focused study of awe in a psychiatrist's empathic listening (EL) assessments and propose an evidence-based framework to study it. Methodology This is an exploratory case series of a psychiatrist's EL interactions (mean duration/x̄ of 46.17 minutes) with six patients (two males and four females) aged 32-72 years (x̄ =54.67, σ = 16.64). Using the method of autoethnography, the verbal and nonverbal aspects of the EL assessments were analyzed and open-coded to generate qualitative data. Results The study revealed that the data in all the case studies could be classed into two thematic groups, namely, mindfulness and transpersonal mindfulness. The emotions of "awe" and "non-agency" were ubiquitous in all six case studies both for the psychiatrist and patients. Conclusions Recognizing the awe and non-agency in EL interaction is essential in conceptualizing the "mindfulness-to-transcendence" framework and the first step toward the evidence-based study of transcendence/metaphysics in phenomenological psychiatry.

14.
Surg Neurol Int ; 15: 56, 2024.
Article in English | MEDLINE | ID: mdl-38468674

ABSTRACT

Background: Lumbar discal pseudocysts are uncommon complications that can arise following lumbar spine surgery. It manifests as a fluid-filled sac near the intervertebral disc, causing pain and discomfort. Understanding its causes, symptoms, and management is crucial for patients and healthcare professionals involved in postoperative spinal care. Case Description A: 35-year-old female developed a discal pseudocyst after undergoing laminectomy and discectomy for lumbar disc herniation. The patient presented with recurrent lower back pain, radiculopathy, and neurological deficit two months post-surgery. Imaging revealed a discal pseudo cyst causing compression of the traversing right L5 nerve root. Given the refractory nature of her symptoms, an endoscopic procedure was offered. Using the transforaminal endoscopic technique, the pseudo cyst was identified and removed, leading to immediate symptomatic relief. Conclusion: This article reports the rare occurrence of discal pseudocyst and highlights the use of endoscopic techniques in its surgical management. Surgeons should be aware of the minimally invasive techniques, as they can offer less morbidity, shorter recovery times, and reduced healthcare costs compared to traditional open surgery.

15.
AJR Am J Roentgenol ; 222(6): e2430927, 2024 06.
Article in English | MEDLINE | ID: mdl-38506538

ABSTRACT

In this 10-patient prospective pilot study, we show the feasibility of pragmatic direct ex vivo measurement of gadolinium retention from group II gadolinium-based contrasts agents (GBCAs) in young patients after routine tooth extraction. This noninvasive method may support future research attempting to understand the link between GBCA exposure and clinical outcomes.


Subject(s)
Contrast Media , Gadolinium , Humans , Gadolinium/pharmacokinetics , Female , Male , Tooth Extraction , Adolescent , Magnetic Resonance Imaging/methods , Mass Spectrometry/methods , Child
16.
Abdom Radiol (NY) ; 49(6): 2145-2154, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38400982

ABSTRACT

PURPOSE: Radiologists with diverse training, specialization, and habits interpret imaging in the Emergency Department. It is necessary to understand if their variation predicts differential value. The purpose of this study was to determine whether attending radiologist variation predicts major clinical outcomes in adult Emergency Department patients imaged with ultrasound for right upper quadrant pain. METHODS: Consecutive ED patients imaged with ultrasound for RUQ pain from 10/8/2016 to 8/10/2022 were included (N = 7097). The primary outcome was prediction of hospital admission by signing attending radiologist. Secondary outcomes included: ED and hospital length of stay (LOS), 30-day mortality, 30-day re-presentation rate, subspecialty consultation, advanced imaging follow up (HIDA, MRI, CT), and intervention (ERCP, drainage or surgery). Sample size was determined a priori (detectable effect size: w = 0.06). Data were adjusted for demographic data, Elixhauser comorbidities, number of ED visits in prior year, clinical data, and system factors (38 covariates). P-values were corrected for multiple comparisons (false discovery rate-adjusted p-values). RESULTS: The included ultrasounds were read by 35 radiologists (median exams/radiologist: 145 [74.5-241.5]). Signing radiologist did not predict hospitalization (p = 0.85), abdominopelvic surgery or intervention within 30 days, re-presentation to the Emergency Department within 30 days, or subspecialty consultation. Radiologist did predict difference in Emergency Department length of stay (p < 0.001) although this difference was small and imprecise. HIDA was mentioned variably by radiologists (range 0-19%, p < 0.001), and mention of HIDA in the ultrasound report increased 10-fold the odds of HIDA being performed in the next 72 h (odds ratio 10.4 [8.0-13.4], p < 0.001). CONCLUSION: Radiologist variability did not predict meaningful outcome differences for patients with right upper quadrant pain undergoing ultrasound in the Emergency Department, but when radiologists mention HIDA in their reports, it predicts a 10-fold increase in the odds a HIDA is performed. Radiologists are relied on for interpretation that shapes subsequent patient care, and it is important to consider how radiologist variability can influence both outcome and resource utilization.


Subject(s)
Abdominal Pain , Emergency Service, Hospital , Radiologists , Ultrasonography , Humans , Female , Male , Middle Aged , Ultrasonography/methods , Radiologists/statistics & numerical data , Abdominal Pain/diagnostic imaging , Retrospective Studies , Adult , Length of Stay/statistics & numerical data , Aged
17.
Int J Surg Pathol ; : 10668969241231973, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38377960

ABSTRACT

Sarcomatoid yolk sac tumor is a very rare histologic type of testicular germ cell tumor and is mainly reported in testicular germ cell tumor patients who receive chemotherapy. Herein, we report an extremely rare concurrent retroperitoneal sarcomatoid yolk sac tumor in a man with a testicular postpuberal teratoma before he received chemotherapy. A 37-year-old man initially presented with a persistent abdominal pain. Subsequent imaging studies revealed a 9.6-cm retroperitoneal mass, and 2 testicular masses (3.1 cm and 0.9 cm in greatest dimension, respectively). His serum tumor markers were within normal ranges. His radical orchiectomy demonstrated a postpubertal type teratoma with an adjacent scarring nodule. Later, his retroperitoneal tumor showed spindle tumor cells embedded in predominantly myxoid and focally fibrous stroma with diffuse and strong immunoreactivity for keratin AE1/AE3, SALL4 and glypican 3. No tumor necrosis or brisk mitotic figures were observed. A diagnosis of sarcomatoid yolk sac tumor was rendered. Fluorescence in situ hybridization analysis of his retroperitoneal sarcomatoid yolk sac tumor revealed polysomy 12 and MYC amplification, whereas no evidence of isochromosome 12p [i(12p)], and DNA sequencing showed 6 mutations per megabase (muts/Mb), and the somatic alterations included ARAF amplification and ATR I774Yfs*5. Considering its rarity, sarcomatoid yolk sac tumor may pose diagnostic challenges. Therefore, relevant clinicoradiologic information and ancillary work up, including immunohistochemistry and molecular studies, may be helpful for the accurate classification. Our tumor further raises awareness of this rare event, expands the spectrum of its clinical presentation, and explores the molecular features.

18.
Cancer Res Commun ; 4(3): 634-644, 2024 03 04.
Article in English | MEDLINE | ID: mdl-38329389

ABSTRACT

Cancer cells exploit the expression of anti-apoptotic protein Bcl-2 to evade apoptosis and develop resistance to therapeutics. High levels of Bcl-2 leads to sequestration of pro-apoptotic proteins causing the apoptotic machinery to halt. In this study, we report discovery of a small molecule, BFC1108 (5-chloro-N-(2-ethoxyphenyl)-2-[(4-methoxybenzyol)amino]benzamide), which targets Bcl-2 and converts it into a pro-apoptotic protein. The apoptotic effect of BFC1108 is not inhibited, but rather potentiated, by Bcl-2 overexpression. BFC1108 induces a conformational change in Bcl-2, resulting in the exposure of its BH3 domain both in vitro and in vivo. BFC1108 suppresses the growth of triple-negative breast cancer xenografts with high Bcl-2 expression and inhibits breast cancer lung metastasis. This study demonstrates a novel approach to targeting Bcl-2 using BFC1108, a small molecule Bcl-2 functional converter that effectively induces apoptosis in Bcl-2-expressing cancers. SIGNIFICANCE: We report the identification of a small molecule that exposes the Bcl-2 killer conformation and induces death in Bcl-2-expressing cancer cells. Selective targeting of Bcl-2 and elimination of cancer cells expressing Bcl-2 opens up new therapeutic avenues.


Subject(s)
Apoptosis Regulatory Proteins , Apoptosis , Humans , Apoptosis Regulatory Proteins/metabolism , Protein Binding
19.
Int J Obes (Lond) ; 48(4): 584-593, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38219005

ABSTRACT

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.


Subject(s)
Cardiovascular Diseases , Gestational Weight Gain , Female , Humans , Pregnancy , Body Mass Index , Cardiovascular Diseases/genetics , Cohort Studies , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Epigenome , European People , Genome-Wide Association Study , Gestational Weight Gain/genetics , Leukocytes , South Asian People , Meta-Analysis as Topic
20.
J Breast Imaging ; 6(2): 141-148, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38170567

ABSTRACT

OBJECTIVE: To determine whether continuity of care between diagnostic breast imaging and subsequent image-guided breast biopsy could reduce patient-reported biopsy-related morbidity. METHODS: This was a prospective, pragmatically randomized, 2-arm health utilities analysis of 200 women undergoing diagnostic breast imaging followed by US- or stereotactic-guided breast biopsy at a single quaternary care center from September 3, 2019, to April 10, 2023. Breast biopsy-naive women with a BI-RADS 4 or 5 finding at diagnostic imaging were randomly scheduled for the typically first available biopsy appointment. One day after biopsy, enrolled patients were administered the Testing Morbidities Index (TMI). The primary outcome was the difference in TMI summary utility scores in patients who did vs did not have the same radiologist perform diagnostic imaging and biopsy. RESULTS: Response rates were 63% (100/159) for the different radiologist cohort and 71% (100/140) for the same radiologist cohort; all respondents answered all questions in both arms. Mean time to biopsy was 7 ± 6 days and 10 ± 9 days, and the number of participating radiologists was 11 and 18, respectively. There was no difference in individual measured domains (pain, fear, or anxiety before procedure; pain, embarrassment, fear, or anxiety during procedure; mental or physical impact after procedure; all P >.00625) or in overall patient morbidity (0.83 [95% CI, 0.81-0.85] vs 0.82 [95% CI: 0.80-0.84], P = .66). CONCLUSION: Continuity of care between diagnostic breast imaging and image-guided breast biopsy did not affect morbidity associated with breast biopsy, suggesting that patients should be scheduled for the soonest available biopsy appointment rather than waiting for the same radiologist.


Subject(s)
Image-Guided Biopsy , Radiologists , Female , Humans , Diagnostic Imaging , Morbidity , Pain , Patient Reported Outcome Measures , Prospective Studies
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