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PURPOSE: Dose-escalation in lung cancer comes with a high risk of severe toxicity. This study aimed to calculate the delivered dose in a Scandinavian phase-III dose-escalation trial. METHODS: The delivered dose was evaluated for 21 locally-advanced non-small cell lung cancer (LA-NSCLC) patients treated as part of the NARLAL2 dose-escalation trial. The patients were randomized between standard and escalated heterogeneous dose-delivery. Both treatment plans were created and approved before randomization. Daily cone-beam CT (CBCT) for patient positioning, and adaptive radiotherapy were mandatory. Standard and escalated plans, including adaptive re-plans, were recalculated on each daily CBCT and accumulated on the planning CT for each patient. Dose to the clinical target volume (CTV), organs at risk (OAR), and the effects of plan adaptions were evaluated for the accumulated dose and on each treated fraction scaled to full treatment. RESULTS: For the standard treatment, plan adaptations reduced the number of patients with CTV-T underdosage from six to one, and the total number of fractions with CTV-T underdosage from 161 to 56; while for the escalated treatment, the number of patients was reduced from five to zero and number of fractions from 81 to 11. For dose-escalation, three patients had fractions exceeding trial constraints for heart, bronchi, or esophagus, and one had an accumulated heart dose above the constraints. CONCLUSION: Dose-escalation for LA-NSCLC patients, using daily image guidance and adaptive radiotherapy, is dosimetrically safe for the majority of patients. Dose calculation on daily CBCTs is an efficient tool to monitor target coverage and OAR doses.
ABSTRACT
Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against Plasmodium falciparum parasites (EC50 = 0.50 µM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC50 = 1.78 µM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.
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Subject(s)
Contact Tracing , Family Characteristics , Mass Screening , Tuberculosis, Pulmonary , Humans , Pakistan/epidemiology , Female , Male , Adult , Prospective Studies , Young Adult , Adolescent , Middle Aged , Child , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/epidemiology , Mass Screening/methods , Child, Preschool , Infant , Tuberculosis/diagnosis , Tuberculosis/epidemiologyABSTRACT
BACKGROUND: Melasma is a chronic pigmentary disorder. In this study, an innovative cream combining cysteamine and tranexamic acid (TXA) was assessed. OBJECTIVE: To evaluate the safety, efficacy, and patient satisfaction of a novel nano-formulated cysteamine and TXA combination cream in treating subjects with epidermal melasma. METHODS: Fifty (50) randomized subjects participated and received cysteamine and TXA combination cream. The cream was applied for 30 minutes daily for a 3-month duration. Treatment effectiveness, safety, patient satisfaction, and adherence were evaluated. RESULTS: A continuous improvement in melasma was observed, with modified Melasma Area and Severity Index (mMASI) scores improving by 40%, 57%, and 63% at 30, 60, and 90 days, respectively. The primary endpoint of a decrease in mMASI scores was met, with 91% of participants experiencing melasma improvement. Patient Satisfaction and Patient Adherence scores indicated satisfaction. Convenience exhibited the strongest correlation with patient adherence. Conclusion: Nano-formulated cysteamine and TXA combination cream showed significant efficacy in decreasing mMASI score while demonstrating a strong safety profile and patient satisfaction. J Drugs Dermatol. 2024;23(7):529-537. doi:10.36849/JDD.7765R1.
Subject(s)
Cysteamine , Medication Adherence , Melanosis , Patient Satisfaction , Tranexamic Acid , Humans , Melanosis/drug therapy , Melanosis/diagnosis , Cysteamine/administration & dosage , Cysteamine/adverse effects , Tranexamic Acid/administration & dosage , Tranexamic Acid/adverse effects , Female , Adult , Treatment Outcome , Middle Aged , Male , Skin Cream/administration & dosage , Skin Cream/adverse effects , Administration, Cutaneous , Severity of Illness Index , Drug Combinations , Nanoparticles/administration & dosage , Young AdultABSTRACT
Whole lung torsion following bilateral lung transplant is a rare complication. This case report describes the diagnostic difficulties and consequences in a 59 year old patient. This study also includes a brief description of other cases in the literature.
ABSTRACT
Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.