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Unlabelled: Unilateral exploration based upon preoperative imaging has become increasingly applied in the management of patients with primary hyperparathyroidism. Unilateral surgical exploration purportedly has high rates of disease control, limited morbidity, and shortened operative time. Unfortunately, significant cohorts of patients with primary hyperparathyroidism are unable to have abnormal glands localized on preoperative imaging evaluation., Aim: The aim of our study was to evaluate the efficacy of Tc(99m) sestamibi preoperative imaging, intraoperative Tc(99m) sestamibi with gamma probe, and intraoperative parathyroid hormone (IOPTH) assessment in a large cohort of patients with primary hyperparathyroidism., Results: A total of 427 patients were prospectively evaluated who were deemed surgical candidates for the treatment of primary hyperparathyroidism. Of these patients, 240 (56%) presented with positive Tc(99m) sestamibi imaging. Another 105 (25%) presented with equivocal Tc(99m) sestamibi imaging. Finally, 82 (19%) presented with negative Tc(99m) sestamibi imaging. Intraoperative rapid assessment of parathyroid hormone was performed at the time of surgical exploration in all patients with negative and equivocal preoperative imaging. All 240 patients with positive preoperative imaging underwent unilateral surgical exploration utilizing intraoperative Tc(99m) sestamibi with gamma probe. The most common finding in the positive Tc(99m) sestamibi scan group was single adenoma in 235 (98%). Normocalcemia was achieved in 233 (97%) of these patients, although in 25 (10%) this was normocalcemia with a persistent elevation in parathyroid hormone (PTH). The most common surgical finding in the equivocal Tc(99m) sestamibi scan group was single adenoma in 85 (81%). Additionally 85 (81%) of these equivocal patients were able to undergo unilateral exploration limited by IOPTH assessment. Normocalcemia was achieved in 101/105 (96%) of patients; although, 10 patients were normocalcemic with persistently elevated PTH and 2 patients had normocalcemia with low PTH. All patients with negative Tc(99m) sestamibi scan underwent bilateral cervical exploration plus IOPTH; 52/82 (63%) were found to have a single adenoma which was the most common surgical finding. Normocalcemia was achieved in 77/82 (94%) of the negative Tc(99m) sestamibi cohort; although 5 patients had normocalcemia with persistently elevated PTH and 2 had normocalcemia with low PTH. Only 3 (0.7%) overall recurrent laryngeal nerve injuries were encountered, and only 1 (0.2%) was permanent. Wound complication rates are reported in detail and were low and comparable for all three Tc(99m) sestamibi imaging based cohorts., Conclusions: Tc(99m) sestamibi preoperative imaging, intraoperative Tc(99m) sestamibi with gamma probe, IOPTH, and combinations of these strategies allow for excellent opportunities for targeted excision of pathologic parathyroid tissue with the least dissection necessary while achieving excellent long-term calcium control and low rates of complication.

Background: Although the Mini Nutritional Assessment (MNA) is recognized as a useful tool for evaluating nutritional status in patients with various diseases, its applicability in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) remains undetermined. Methods: We designed a prospective cross-sectional study to investigate whether the MNA Short-Form (MNA-SF) score can serve as a screening tool to assess the nutritional status of patients with NTM-PD. The MNA-SF was conducted upon patient enrollment, and correlation analyses were performed to compare MNA-SF scores with other nutritional measurements and disease severity. Multivariable logistic regression analyses were conducted to evaluate the association between MNA-SF scores and NTM-PD severity. Results: The 194 patients with NTM-PD included in the analysis had a median age of 65.0 (59.0–69.0) years; 59.3% (n = 115) had low MNA-SF scores (< 12). The low MNA-SF group exhibited a lower body mass index (19.7 vs. 22.4 kg/m2, p < 0.001) and fat-free mass index (14.7 vs. 15.6 kg/m2, p < 0.001) than the normal MNA-SF group, as well as higher incidences of sarcopenia (20.0% vs. 6.3%, p = 0.008) and adipopenia (35.7% vs. 5.1%, p < 0.001). However, no significant differences in calorie and protein intakes were observed between the two groups. Low MNA-SF scores were associated with radiographic severity (adjusted odds ratio 2.72, 95% confidence interval 1.38–5.36) but not with forced vital capacity. Conclusions: The MNA-SF can effectively assess the nutritional status of patients with NTM-PD and can serve as an important clinical indicator in NTM-PD where treatment timing is determined by clinical judgment. [ABSTRACT FROM AUTHOR]

Legal approaches to civil commitment in the United States and the United Kingdom are compared. A concise overview of the historical evolution of civil commitment in both countries precedes a discussion of the present scheme of commitment standards in each system. These current standards in U.S. and U.K. jurisdictions are then applied to a hypothetical case of delusional disorder. A discussion of the constructive use of civil commitment in patients with delusional disorder who may be dangerous focuses on its value as a preventive measure against potential harm to self or others, as well as the pros and cons of coercive assessment and treatment. Despite the many differences in approach to commitment, the authors concur that in both countries the patient with delusional disorder was committable before the commission of a serious criminal offense.

The use of complementary and alternative medicine (CAM) in developed countries has increased significantly over the years. Among the most popular are the weight loss supplements or "fat burners." Liver failure due to these popular remedies has been widely recognized. Usnic acid has been an ingredient of dietary supplements that cause liver failure. Its hepatotoxicity has not been recognized because it is usually mixed with other ingredients that are presumably hepatotoxic. We describe a case of a 28-yr-old woman who presented with fulminant liver failure requiring orthotopic liver transplantation, after taking pure usnic acid for weight loss. This is the first report on fulminant liver failure associated with the ingestion of pure usnic acid. A discussion about hepatotoxicity of the different compounds of dietary supplements is presented. This is a reminder for the clinicians about the potential side effects of CAM.

De Clérambault's Syndrome or Erotomania was originally described as a delusional disorder in which a woman believes that an older man of higher social status is passionately in love with her. The patient's relentless pursuit of the delusional love object, often with escalating intrusiveness, may eventually involve threats or overt acts of retaliation, in response to repeated rejection, unrequited love, or alleged betrayal. Cases from the literature are reviewed in which the delusional romantic attachment involves the patient's psychiatrist or another medical specialist. The authors present a case involving a patient suffering from erotomania who develops a delusional fixation on her psychiatrist and, after her advances are repeatedly rejected, sues him for malpractice, alleging she had a sexual relationship with him in the course of treatment. The implications of the litigious paranoid, who uses the legal system to act out delusional concerns and retaliatory fantasies, are discussed. This is the first known case of an erotomanic patient claiming malpractice on the grounds that her psychiatrist had a sexual relationship with her.

Paranoid symptomatology involving suspicions, a sense of being wronged and persecuted, along with an implacable will to retaliate against one's enemies, often translates into litigious struggles. Paranoids resort to the judicial arena to act out their own internal psychopathologic needs. Examples are offered of the many ways litigious paranoids may present within the legal system, as well as how interventions by the psychiatrist may be useful. Criminal behavior by paranoids, under the sway of full-blown delusions of various types, is discussed and analyzed. Historical cases are described (Hadfield, M'Naghten), and more contemporary cases are discussed according to diagnostic subtypes. The central importance of paranoid delusions in insanity defense cases and the exculpatory effect of various delusional subtypes are examined.

The authors discuss the general outlines of the Tarasoff duty of psychotherapists to protect potential victims of their violent patients. They describe the flexible range of clinical responses that therapists have utilized, as well as their professional concerns about preserving patient confidentiality (or at least strictly circumscribing the scope of disclosure when confidentiality must be breached). A recent case is reported that illustrates a striking new extension of Tarasoff, involving a police search and seizure of a psychotherapist's confidential treatment records and tapes, in response to a third-party complaint that the records contained evidence of his patients' violent acts and propensities. The implications of this case are that the therapist's discretion in the assessment of his duty to protect, the selection of a proper course of action, and the implementation of specific responses may be taken out of his hands, for all intents and purposes, and expropriated by law and order officials. Moreover, regardless of whatever clinical approach he adopts and whether or not he issues a warning, his attempts to preserve patient confidentiality are bound to prove unsuccessful in any future legal proceedings. Patient communications are likely to lose their confidential status on the grounds that they caused or triggered the Tarasoff warning (or that they should have triggered it). If the patient directed serious threats against the therapist himself, the court may find that, as a consequence, a "genuine therapeutic relationship" ceased to exist and thereafter all patient disclosures were no longer confidential on that basis.(ABSTRACT TRUNCATED AT 250 WORDS)

The legal context of voluntary and involuntary intoxication is delineated. The author reports a case of involuntary intoxication involving scopolamine toxic psychosis or delirium, in which he testified as a psychiatric expert witness. The specific psychological and physiological symptomatology produced by scopolamine intoxication is outlined. The forensic psychiatrist should be alert to the involuntary intoxication defense in these cases and should familiarize himself with the specific toxicity of scopolamine, in view of the significant increase in the number of incidents in which it is utilized as "knockout" drops in certain jurisdictions.

The R-CRAS (Rogers' Criminal Responsibility Assessment Scales) purports to be a systematic and empirically based approach to evaluations of criminal responsibility. This 'insanity detector' has been heralded as a reliable instrument in the resolution of the psycholegal controversies surrounding the plea of insanity. It is contended that, regardless of its possible scientific merit, most courts will find that the R-CRAS fails to satisfy the Frye test for admissibility of novel scientific evidence (that is, general acceptance by the relevant scientific community). Moreover, it is argued that the R-CRAS's potential for prejudice outweighs its probative value, in that it might unfairly bolster the testimony of the expert witness who relies upon it and might overwhelm the jury because of its 'aura of special reliability and trustworthiness'. Until such time as the R-CRAS does gain widespread acceptance and is shown to be sufficiently reliable to outweigh any potential prejudice (if ever), the author is of the opinion that forensic psychiatrists and psychologists may have to continue to conduct evaluations of criminal responsibility 'the old-fashioned way'. 'Truth does less good in the world than its appearances do harm' --La Rochefoucauld.

The purpose of this study was to develop and test the reliability and validity of a brief and comprehensive instrument to assess self-management, decision-making, and coping by chronic obstructive pulmonary disease (COPD) patients. A web-based questionnaire was administered to 300 COPD patients and a retest was administered to 100 COPD patients. Cronbach's alpha was used to assess internal consistency, and an intraclass correlation coefficient was calculated to test the reliability of the retest. The convergent and discriminant validities were also examined. Valid responses were obtained from 279 participants in the first survey and 70 participants in the retest. From our analysis, a COPD self-care assessment scale (CSCS) was developed, consisting of seven subscales and 14 items. Cronbach's alpha for the total CSCS score, intraclass correlation coefficient, and scale success rate were 0.80, 0.79, and 100%, respectively. A multivariate analysis showed that CSCS was associated with current smoking (standardized partial regression coefficient [std β] = -0.30; p < 0.001), long-term oxygen therapy (std β = 0.23; p < 0.001), and social support (std β = 0.24; p < 0.001), but not psychological symptoms or quality of life. The CSCS is also useful in assessing self-management, decision-making, and coping in Japanese COPD patients, and the scale has high reliability and validity. [ABSTRACT FROM AUTHOR]

Introduction: BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, through its direct catalytic activity on the repressive epigenetic mark histone H2AK119ub, as well as on several other substrates. BAP1 is also a highly important tumor suppressor, expressed and functional across many cell types and tissues. In recent work, we demonstrated a cell intrinsic role of BAP1 in the B cell lineage development in murine bone marrow, however the role of BAP1 in the regulation of B cell mediated humoral immune response has not been previously explored. Methods and results: In the current study, we demonstrate that a B-cell intrinsic loss of BAP1 in activated B cells in the Bap1fl/fl Cg1-cre murine model results in a severe defect in antibody production, with altered dynamics of germinal centre B cell, memory B cell, and plasma cell numbers. At the cellular and molecular level, BAP1 was dispensable for B cell immunoglobulin class switching but resulted in an impaired proliferation of activated B cells, with genome-wide dysregulation in histone H2AK119ub levels and gene expression. Conclusion and discussion: In summary, our study establishes the B-cell intrinsic role of BAP1 in antibody mediated immune response and indicates its central role in the regulation of the genome-wide landscapes of histone H2AK119ub and downstream transcriptional programs of B cell activation and humoral immunity. [ABSTRACT FROM AUTHOR]

Pulmonary rehabilitation (PR) increases exercise capacity, reduces dyspnea, and improves quality of life (QoL) in patients with chronic obstructive pulmonary disease (COPD). Patients requiring PR can present with multiple comorbidities. One of the most common comorbidities is obesity. The prevalence of obesity in patients with COPD is increasing at an alarming rate. To date the efficacy of PR to ameliorate obesity in patients with COPD is unclear. Obesity in patients with COPD is associated with increased morbidity and mortality compared to patients without obesity. However, the benefits of obesity paradox in lower mortality rate health-related QoL and health care utilization remain unclear. This review discusses the challenges of prescribing PR to patients with obesity and COPD. In addition, the definition of and the potential challenges and benefits of the obesity paradox in patients with COPD will be discussed. Treatment strategies that include combining PR with lifestyle management, individually tailored nutritional advice, pharmacotherapy, and surgery need to be tested in prospective, randomized controlled trials. The challenges of providing complex care, prioritizing patient needs, and future directions will also be discussed for patients with obesity and COPD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In many countries, health care professionals are legally obliged to share information from electronic health records with patients. However, concerns have been raised regarding the sharing of notes with adolescents in mental health care, and health care professionals have called for recommendations to guide this practice. Objective: The aim was to reach a consensus among authors of scientific papers on recommendations for health care professionals' digital sharing of notes with adolescents in mental health care and to investigate whether staff at child and adolescent specialist mental health care clinics agreed with the recommendations. Methods: A Delphi study was conducted with authors of scientific papers to reach a consensus on recommendations. The process of making the recommendations involved three steps. First, scientific papers meeting the eligibility criteria were identified through a PubMed search where the references were screened. Second, the results from the included papers were coded and transformed into recommendations in an iterative process. Third, the authors of the included papers were asked to provide feedback and consider their agreement with each of the suggested recommendations in two rounds. After the Delphi process, a cross-sectional study was conducted among staff at specialist child and adolescent mental health care clinics to assess whether they agreed with the recommendations that reached a consensus. Results: Of the 84 invited authors, 27 responded. A consensus was reached on 17 recommendations on areas related to digital sharing of notes with adolescents in mental health care. The recommendations considered how to introduce digital access to notes, write notes, and support health care professionals, and when to withhold notes. Of the 41 staff members at child and adolescent specialist mental health care clinics, 60% or more agreed with the 17 recommendations. No consensus was reached regarding the age at which adolescents should receive digital access to their notes and the timing of digitally sharing notes with parents. Conclusions: A total of 17 recommendations related to key aspects of health care professionals' digital sharing of notes with adolescents in mental health care achieved consensus. Health care professionals can use these recommendations to guide their practice of sharing notes with adolescents in mental health care. However, the effects and experiences of following these recommendations should be tested in clinical practice. [ABSTRACT FROM AUTHOR]

Historically, treatment of chronic, nonhealing wounds has focused on managing symptoms using biomaterial‐based wound dressings, which do not adequately address the underlying clinical issue. Mesenchymal stem cells (MSCs) are a promising cell‐based therapy for the treatment of chronic, nonhealing wounds, yet inherent cellular heterogeneity and susceptibility to death during injection limit their clinical use. Recently, researchers have begun to explore the synergistic effects of combined MSC‐biomaterial therapies, where the biomaterial serves as a scaffold to protect the MSCs and provides physiologically relevant physicochemical cues that can direct MSC immunomodulatory behavior. In this review, we highlight recent progress in this field with a focus on the most commonly used biomaterials, classified based on their source, including natural biomaterials, synthetic biomaterials, and the combination of natural and synthetic biomaterials. We also discuss current challenges regarding the clinical translation of these therapies, as well as a perspective on the future outlook of the field. [ABSTRACT FROM AUTHOR]

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies. [ABSTRACT FROM AUTHOR]

Background: Given the deleterious effects of physical inactivity in persons with chronic obstructive pulmonary disease (COPD) and/or heart failure (HF), interventions that promote long-term daily physical activity are needed. Mindful Steps, designed to promote walking behaviors in COPD and HF, is a multicomponent intervention that integrates mind-body content with other self-regulatory components. The aim of the current qualitative study was to characterize participants' experiences with Mindful Steps and understand the perceived influence of the intervention on walking and health. Method: In the context of a pilot randomized controlled feasibility trial comparing the year-long Mindful Steps program to usual care among individuals with COPD and HF, semi-structured qualitative interviews were administered at 6- and 12-months. Interviews were audio recorded and transcribed. The constant comparative method was used to code transcripts, identify categories, and develop interrelated themes. Results: Nineteen participants (63% female; M age = 70.2 years, SD = 6.95) who were randomized to the intervention group completed the 6-month interview and 17 completed the 12-month interview. The pedometer with feedback, live group classes, and mind-body videos were described as the most helpful intervention components. Participants learned several strategies that helped their walking (e.g., breathing regulation and awareness, body awareness, mind-body techniques, pacing), described walking as enjoyable, and identified internal reasons for walking (e.g., to feel good). They also reported several physical and mental health benefits of the intervention. Some participants reported limited influence of the intervention on walking or health. Many participants continued to use the strategies they learned in the first half of the intervention at 12-months. Conclusions: The mind-body content of Mindful Steps appeared to positively influence walking behaviors. Participants' experiences with the intervention helped to identify areas for future intervention refinement. Future quantitative work is needed to corroborate these qualitative findings and assess the efficacy of the intervention on long-term physical activity engagement. Trial Registration: This trial is registered in Clinical Trials.gov, ID number NCT01551953. [ABSTRACT FROM AUTHOR]

Background: Reduced mobility is a central feature of COPD. Assessment of mobility outcomes that can be measured digitally (digital mobility outcomes (DMOs)) in daily life such as gait speed and steps per day is increasingly possible using devices such as pedometers and accelerometers, but the predictive value of these measures remains unclear in relation to key outcomes such as hospital admission and survival. Methods: We conducted a systematic review, nested within a larger scoping review by the MOBILISE-D consortium, addressing DMOs in a range of chronic conditions. Qualitative and quantitative analysis considering steps per day and gait speed and their association with clinical outcomes in COPD patients was performed. Results: 21 studies (6076 participants) were included. Nine studies evaluated steps per day and 11 evaluated a measure reflecting gait speed in daily life. Negative associations were demonstrated between mortality risk and steps per day ( per 1000 steps) (hazard ratio (HR) 0.81, 95% CI 0.75–0.88, p<0.001), gait speed (<0.80 m·s−1 ) (HR 3.55, 95% CI 1.72–7.36, p<0.001) and gait speed ( per 1.0 m·s−1 ) (HR 7.55, 95% CI 1.11–51.3, p=0.04). Fewer steps per day ( per 1000) and slow gait speed (<0.80 m·s−1 ) were also associated with increased healthcare utilisation (HR 0.80, 95% CI 0.72–0.88, p<0.001; OR 3.36, 95% CI 1.42–7.94, p=0.01, respectively). Available evidence was of low-moderate quality with few studies eligible for meta-analysis. Conclusion: Daily step count and gait speed are negatively associated with mortality risk and other important outcomes in people with COPD and therefore may have value as prognostic indicators in clinical trials, but the quantity and quality of evidence is limited. Larger studies with consistent methodologies are called for. [ABSTRACT FROM AUTHOR]

The domains of mental health and artificial intelligence (AI) are undergoing rapid advancements, exhibiting the capacity to mutually influence one another in significant ways. The increasing prevalence of mental health illnesses has prompted the exploration of potential remedies in the field of AI, which show promise in the areas of early detection, prevention, and therapy. Sophisticated machine learning algorithms possess the capability to evaluate extensive volumes of data, including social media posts and voice patterns, with the objective of detecting patterns and symptoms associated with mental illness. This facilitates the implementation of more focused interventions and individualized treatment strategies. Furthermore, chatbots utilizing AI have the capability to deliver round-the-clock assistance to those undergoing acute distress or grant them access to therapy in cases where waiting lists are extensive. Nevertheless, it is of utmost importance to guarantee the incorporation of ethical issues throughout the use of AI in the field of mental healthcare. In order to achieve successful integration, it is imperative to address many concerns, including but not limited to privacy, bias, and accurate diagnosis. However, the convergence of mental health and AI offers a distinct prospect to transform our approach to mental disease and improve the availability of care for countless individuals globally. [ABSTRACT FROM AUTHOR]

Background Depression is known to limit physical activity (PA) among individuals with chronic obstructive pulmonary disease (COPD). However, whether and how depression influences the effectiveness of PA interventions is unknown. Purpose The study examined the association between baseline depression symptoms and change in daily step count and whether group assignment to a web-based, pedometer-mediated PA intervention moderated the association between baseline depression symptoms and change in daily step count. Methods Secondary analysis included two cohorts of U.S. Veterans with COPD (n = 212; 97% male; mean age 69 ± 8 years) assessed at baseline and 3 months. Cohorts 1 and 2 were randomly assigned to the same PA intervention (n = 111) or a control group (n = 101). Multivariate regressions tested the main effects of baseline depression symptoms (BDI-II total and cognitive-affective and somatic subscales) on change in daily steps, as well as the interaction between baseline BDI-II and subscales and group assignment on change in daily steps. Results Greater BDI-II total score (B = −31.8, SE = 14.48, p =.030) and somatic subscale scores (B = −99.82, SE = 35.76, p =.006) were associated with less improvement in daily step count. There was a significant interaction between baseline cognitive-affective subscale and the intervention predicting change in daily step count (B = −88.56, SE = 42.31, p =.038). When cognitive-affective subscale scores were ≥1 SD above the mean, the intervention was no longer associated with an increase in daily step count (p =.585). Conclusions Depression should be routinely assessed and targeted as part of PA promotion efforts. [ABSTRACT FROM AUTHOR]

Summary: Adaptor chimeric antigen receptor (CAR) T‐cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T‐cell therapy in myeloid malignancies. The adaptor CAR T‐cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well‐tolerated, rapidly switchable, CD123‐directed UniCAR T‐cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti‐tumour responses, underlining the need to further design alternative AML‐specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS‐like tyrosine kinase 3 (FLT3)‐directed UniCAR T‐cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half‐life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3‐specific UniCAR T cells for the therapy of AML. [ABSTRACT FROM AUTHOR]

In vascular reconstruction in arterial trauma, ruptured abdominal aortic aneurysm or ruptured aneurysmal arteriovenous fistula, the challenge no longer lies in the surgical procedure itself, but rather the prevention of intimal hyperplasia, thrombosis and aneurysm formation, in parallel with extending as long as possible the patency of the grafts. of this study is to present the preliminary findings of a novel non-ionizing radiation-based therapeutic method for stabilizing and strengthening the extracellular matrix of the venous wall, improving the biomechanical profile of the autologous graft used in myocardial and lower limb revascularization. We developed the protocol and method for UV-A irradiation as a new method of mechanical augmentation of the resistance structure of the venous graft. Samples of the superficial femoral artery, superficial femoral vein, and great saphenous vein (GSV) were extracted from a 58-year-old patient who underwent above-the-knee amputation, and were prepared in 5 × 5 cm2 patches. Additionally, we analyzed the samples biomechanically biaxially with the BioTester® 5000, in which we established a 25% equibiaxial stretch. The GSV sample was also treated by UV-A irradiation after being kept in riboflavin 5′-phosphate monosodium salt for 30 min. After UV-A treatment of the GSV wall, we observed an important increase of Cauchy stress from 82 kPa to 131 kPa in the longitudinal axis and from 66 kPa to 115 kPa in the circumferential axis. Young's modulus also changed after treating the GSV wall from 0.564 MPa to 1.218 MPa (longitudinal) and from 0.397 MPa to 0.709 MPa (circumferential). As a result of the therapy, we observed a considerable similarity of the mechanical behavior of the GSV wall to that of the artery wall. The photocrosslinking of collagen fibbers at the vein graft adventitia hardens and stiffens the venous wall, making it behave like the arterial wall after treatment. These preliminary ex vivo results on human vascular tissue may serve as the foundation for the development of new treatment approaches utilizing mechanical augmentation of the vein grafts. [ABSTRACT FROM AUTHOR]

The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of the first comprehensive sequencing efforts from The Cancer Genome Atlas (TCGA), which revealed that dozens of unique genes are recurrently mutated in AML genomes. Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets FLT3 and IDH1/2 mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting TP53-mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024. [ABSTRACT FROM AUTHOR]

MUC12 is a transmembrane mucin that is highly expressed in >50% of primary and metastatic colorectal tumors. MUC12 is also expressed by normal epithelial cells of the colon and small intestine. Although MUC12 localization in normal epithelial cells is restricted to the apical membrane, expression in tumors is depolarized and shows broad membrane localization. The differential localization of MUC12 in tumor cells as compared with normal cells makes it a potential therapeutic target. Here, we evaluated targeting of MUC12 with a BiTE (bispecific T-cell engager) molecule. We generated a panel of proof-of-concept half-life extended (HLE) BiTE molecules that bind MUC12 on tumor cells and CD3 on T cells. We prioritized one molecule based on in vitro activity for further characterization in vivo In vitro , the MUC12 HLE BiTE molecule mediated T-cell-redirected lysis of MUC12-expressing cells with half-maximal lysis of 4.4 ± 0.9 to 117 ± 78 pmol/L. In an exploratory cynomolgus monkey toxicology study, the MUC12 HLE BiTE molecule administered at 200 μg/kg with a step dose to 1,000 μg/kg was tolerated with minimal clinical observations. However, higher doses were not tolerated, and there was evidence of damage in the gastrointestinal tract, suggesting dose levels projected to be required for antitumor activity may be associated with on-target toxicity. Together, these data demonstrate that the apically restricted expression of MUC12 in normal tissues is accessible to BiTE molecule target engagement and highlight the difficult challenge of identifying tumor-selective antigens for solid tumor T-cell engagers., (©2021 American Association for Cancer Research.)