A phase 2 trial of zanidatamab in HER2-overexpressed advanced endometrial carcinoma and carcinosarcoma (ZW25-IST-2).

OBJECTIVE: HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment. METHODS: We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed. RESULTS: This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated. CONCLUSIONS: We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy. CLINICALTRIALS: govidentifier: NCT04513665.

Procedural interventions for oligoprogression during treatment with immune checkpoint blockade in gynecologic malignancies: a case series.

OBJECTIVE: To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade. METHODS: Patients with gynecologic cancers treated with immune checkpoint blockade between January 2013 and October 2021 who underwent procedural interventions including surgical resection, interventional radiology ablation, or radiation therapy for oligoprogressive disease were identified. Procedures performed before immune checkpoint therapy initiation or ≥6 months after therapy completion were excluded. Long immunotherapy duration prior to intervention was defined as ≥6 months. Progression-free survival and overall survival were calculated from procedure date until disease progression or death, respectively. RESULTS: During the study period, 886 patients met inclusion criteria and received immune checkpoint blockade therapy. Of these, 34 patients underwent procedural interventions for oligoprogressive disease; 7 underwent surgical resection, 3 underwent interventional radiology ablation, and 24 underwent radiation therapy interventions. Primary disease sites included uterus (71%), ovary (24%), and cervix (6%). Sites of oligoprogression included abdomen/pelvis (26%), bone (21%), lung (18%), distant lymph node (18%), brain (9%), liver (6%), and vagina (3%). Most tumors (76%) did not exhibit microsatellite instability or mismatch repair deficiency. Approximately half (53%) of the patients had long immune checkpoint therapy duration prior to intervention. Median progression-free survival following the procedure was 5.3 months (95% CI, 3.1-9.9), and median overall survival was 21.7 months (95% CI, 14.9-not estimable). Long versus short immune checkpoint therapy duration prior to procedure and length of immune checkpoint therapy had no effect on progression-free or overall survival. CONCLUSIONS: Procedural interventions for patients with oligoprogression on immune checkpoint blockade therapy are feasible and demonstrate favorable outcomes. With expanding use of immune checkpoint therapy, it is important to investigate combined modalities to maximize therapeutic benefit for patients with gynecologic cancers.

Metal-Organic Frameworks Constructed from Branched Oligomers.

Metal-organic frameworks (MOFs) prepared from oligomeric or polymeric organic ligands have been studied and are termed oligoMOFs and polyMOFs, respectively. Herein, several oligoMOFs are described that have been prepared from branched oligomers with dendritic or star-like architectures. Branched oligomeric ligands with four (4(H2bdc)-b) or eight (8(H2bdc)-b) 1,4-benzene dicarboxylic acid (H2bdc) groups were prepared and used to synthesize isoreticular-type Zn(II)-based MOFs (IRMOF). A branched tetramer (4(H2bdc)-b) produced an oligoIRMOF-1 with improved ambient stability compared with IRMOF-1 or previously described oligoMOFs. To understand the effect of the ligand architecture, oligoIRMOFs were also prepared from a linear tetramer (4(H2bdc)-l). For a branched octamer (8(H2bdc)-b), it was found that the addition of an organic base was required to produce crystalline oligoIRMOFs. Multivariate MOFs (MTV-MOFs) could also be readily prepared with a combination of an octamer (8(H2bdc)-b) and H2bdc.

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

Comparison of ChatGPT and Traditional Patient Education Materials for Men's Health.

INTRODUCTION: ChatGPT is an artificial intelligence platform available to patients seeking medical advice. Traditionally, urology patients consulted official provider-created materials, particularly the Urology Care Foundation™ (UCF). Today, men increasingly go online due to the rising costs of health care and the stigma surrounding sexual health. Online health information is largely inaccessible to laypersons as it exceeds the recommended American sixth to eighth grade reading level. We conducted a comparative assessment of patient education materials generated by ChatGPT vs UCF regarding men's health conditions. METHODS: All 6 UCF men's health resources were identified. ChatGPT responses were generated using patient questions obtained from UCF. Adjusted ChatGPT responses were generated by prompting, "Explain it to me like I am in sixth grade." Textual analysis was performed using sentence, word, syllable, and complex word count. Six validated formulae were used for readability analysis. Two physicians independently scored responses for accuracy, comprehensiveness, and understandability. Statistical analysis involved Wilcoxon matched-pairs test. RESULTS: ChatGPT responses were longer and more complex. Both UCF and ChatGPT failed official readability standards, although ChatGPT performed significantly worse across all 6 topics (all P < .001). Conversely, adjusted ChatGPT readability typically surpassed UCF, even meeting the recommended level for 2 topics. Qualitatively, UCF and ChatGPT had comparable accuracy, although ChatGPT had better comprehensiveness and worse understandability. CONCLUSIONS: When comparing readability, ChatGPT-generated education is less accessible than provider-written content, although neither meets the recommended level. Our analysis indicates that specific artificial intelligence prompts can simplify educational materials to meet national standards and accommodate individual literacy.

Reversible Postsynthetic Modification in a Metal-Organic Framework.

Postsynthetic modification (PSM) of metal-organic frameworks (MOFs) provides access to functional materials and advanced porous solid engineering. Herein, we report the reversible PSM of a multivariate isoreticular MOF by applying dynamic furan-maleimide Diels-Alder (DA) chemistry. The key step involves incorporating a furan group into the MOF via "click" PSM, which can then undergo repeated cycles of modification and de-modification with maleimides. The structural integrity, crystallinity, and porosity of the furan-appended MOF remained intact even after three consecutive PSM/de-modification cycles using three different functionalized maleimides.

Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats.

Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.

Correction: Self-healing mixed matrix membranes containing metal-organic frameworks.

[This corrects the article DOI: 10.1039/D2SC04345A.].

Erratum: Further correction: Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.

[This corrects the article DOI: 10.1039/C9SC05586J.].

Confirmation and refutation of very luminous galaxies in the early Universe.

During the first 500 million years of cosmic history, the first stars and galaxies formed, seeding the Universe with heavy elements and eventually reionizing the intergalactic medium1-3. Observations with the James Webb Space Telescope (JWST) have uncovered a surprisingly high abundance of candidates for early star-forming galaxies, with distances (redshifts, z), estimated from multiband photometry, as large as z ≈ 16, far beyond pre-JWST limits4-9. Although such photometric redshifts are generally robust, they can suffer from degeneracies and occasionally catastrophic errors. Spectroscopic measurements are required to validate these sources and to reliably quantify physical properties that can constrain galaxy formation models and cosmology10. Here we present JWST spectroscopy that confirms redshifts for two very luminous galaxies with z > 11, and also demonstrates that another candidate with suggested z ≈ 16 instead has z = 4.9, with an unusual combination of nebular line emission and dust reddening that mimics the colours expected for much more distant objects. These results reinforce evidence for the early, rapid formation of remarkably luminous galaxies while also highlighting the necessity of spectroscopic verification. The large abundance of bright, early galaxies may indicate shortcomings in current galaxy formation models or deviations from physical properties (such as the stellar initial mass function) that are generally believed to hold at later times.

Unravelling Ultrafast Li Ion Transport in Functionalized Metal-Organic Framework-Based Battery Electrolytes.

Nonaqueous fluidic transport and ion solvation properties under nanoscale confinement are poorly understood, especially in ion conduction for energy storage and conversion systems. Herein, metal-organic frameworks (MOFs) and aprotic electrolytes are studied as a robust platform for molecular-level insights into electrolyte behaviors in confined spaces. By employing computer simulations, along with spectroscopic and electrochemical measurements, we demonstrate several phenomena that deviate from the bulk, including modulated solvent molecular configurations, aggregated solvation structures, and tunable transport mechanisms from quasi-solid to quasi-liquid in functionalized MOFs. Technologically, taking advantage of confinement effects may prove useful for addressing stability concerns associated with volatile organic electrolytes while simultaneously endowing ultrafast transport of solvates, resulting in improved battery performance, even at extreme temperatures. The molecular-level insights presented here further our understanding of structure-property relationships of complex fluids at the nanoscale, information that can be exploited for the predictive design of more efficient electrochemical systems.

Case Report: A Parotid Abscess With Otorrhea, Drainage via the Fissure of Santorini.

We report a case of a healthy 62-year-old male with no identifiable risk factors who presented with a 2-week history of progressive unilateral parotid gland enlargement and tenderness followed by subsequent otorrhea. A computed tomography scan and ultrasound confirmed a markedly enlarged posterior aspect of the parotid gland with the evidence of necrosis. The culture of aspirated fluid grew Staphylococcus aureus. Purulent fluid was then noted draining from the external auditory canal, via the fissure of Santorini. The patient was treated with antibiotics, pain management, and daily parotid massage with complete resolution of the parotitis. Acute bacterial parotitis with subsequent drainage and otorrhea through the fissures of Santorini is rare, with only a few reported cases in the literature.

Quantifying Ligand Binding to the Surface of Metal-Organic Frameworks.

The binding of molecules to the exterior surface of metal-organic frameworks (MOFs) is not a well-understood phenomenon. Herein, the surface chemistry of three MOFs, UiO-66, MIL-88B-NH2, and ZIF-8, is investigated using dye-displacement experiments. MOF particle surfaces were modified with ligand-appended BODIPY dyes. The ability of the coordinated dyes to be displaced by a variety of exogenous ligands was measured by ultraviolet-visible spectroscopy. This method allowed for measurement of apparent binding constants for different ligands to the MOF surface. As might be expected, ligand affinity was dependent on the nature of the underlying metal-ligand composition of the MOF. This work provides a quantitative evaluation of ligand binding to MOF surfaces and important insights for the modulation, modification, and manipulation of MOFs.

Analysis of patient education materials on TikTok for erectile dysfunction treatment.

Erectile dysfunction (ED) is widely prevalent and has diverse management options which are poorly understood and accessed by patients. This cross-sectional TikTok study aimed to evaluate the quality of ED educational materials and define trends in healthcare provider content development. Three reviewers independently analyzed 50 videos. Variables of interest included author characteristics, viewer engagement, content accuracy, and video quality, understandability, and actionability. Quantitative analysis was performed using the validated PEMAT and DISCERN screening tools. A wide range of treatment options were presented among the 26 healthcare and 24 non-healthcare videos, including behavioral techniques, herbs/ supplements, dietary modifications, pharmacology, and interventions. Healthcare authors tended to focus on pharmacology and intervention, and when they did discuss behavioral, herbal, or dietary options, accuracy significantly exceeded non-healthcare authors (96.2% vs. 12.5%, p < 0.001). Although healthcare-authored videos were superior in accuracy and understandability scores (p < 0.001), they had low actionability and reduced user engagement including likes (1195 vs. 4723, p = 0.050) and bookmarks (114 vs. 839, p = 0.010). Our findings indicate that despite the availability of high-quality ED treatment resources created by healthcare professionals on TikTok, engagement and actionability remain alarmingly low. Furthermore, there is substantial, readily accessible misinformation produced by non-healthcare entities. Modernized medical education paradigms, communications research, and awareness may optimize social media as a public health tool.

A computational analysis on the impact of multilevel laryngotracheal stenosis on airflow and drug particle dynamics in the upper airway.

Laryngotracheal stenosis (LTS) is a type of airway narrowing that is frequently caused by intubation-related trauma. LTS can occur at one or multiple locations in the larynx and/or trachea. This study characterizes airflow dynamics and drug delivery in patients with multilevel stenosis. Two subjects with multilevel stenosis (S1 = glottis + trachea, S2 = glottis + subglottis) and one normal subject were retrospectively selected. Computed tomography scans were used to create subject-specific upper airway models. Computational fluid dynamics modeling was used to simulate airflow at inhalation pressures of 10, 25, and 40 Pa, and orally inhaled drug transport with particle velocities of 1, 5, and 10 m/s, and particle size range of 100 nm-40 µm. Subjects had increased airflow velocity and resistance at stenosis with decreased cross-sectional area (CSA): S1 had the smallest CSA at trachea (0.23 cm2) and resistance = 0.3 Pa·s/mL; S2 had the smallest CSA at glottis (0.44 cm2), and resistance = 0.16 Pa·s/mL. S1 maximal stenotic deposition was 4.15% at trachea; S2 maximal deposition was 2.28% at glottis. Particles of 11-20 µm had the greatest deposition, 13.25% (S1-trachea) and 7.81% (S2-subglottis). Results showed differences in airway resistance and drug delivery between subjects with LTS. Less than 4.2% of orally inhaled particles deposited at stenosis. Particle sizes with most stenotic deposition were 11-20 µm and may not represent typical particle sizes emitted by current-use inhalers.

Self-Reported Dysphagia and Psychosocial Health Among Community-Dwelling Older Adults: Results of a National Study.

BACKGROUND: The risk of dysphagia increases with age, affecting up to 33% of adults over the age of 65. Older adults with dysphagia are at increased risk for negative physical health outcomes such as aspiration pneumonia and death. However, the relationship between dysphagia and psychosocial health is uncertain in this population. OBJECTIVE: We aimed to assess the associations between dysphagia and psychosocial health among older adults (≥ 65) with self-reported dysphagia. DESIGN: We performed a cross-sectional assessment of the National Health and Aging Trends Study (NHATS) conducted in 2019. MAIN MEASURES: Weighted logistic and linear regression models were used to assess the relationship between self-reported dysphagia and psychosocial health using established patient-reported outcome measures including those for depression, anxiety, and social isolation previously used in NHATS analyses, while adjusting for demographics, comorbid conditions, and risk factors for dysphagia identified by purposeful selection. KEY RESULTS: Among the 4041 adults in this cohort, almost half (40%) were between 70 and 74 years old, more than half were female (55%), and a significantly higher proportion were White, non-Hispanic respondents (78.1%, p < 0.01) compared with other races and ethnicities. There were 428 (10.5%) respondents reporting dysphagia symptoms within the previous month. In the multivariable model, dysphagia was associated with significantly increased odds of anxiety (OR 1.33 [1.06, 1.67]) and a significantly decreased sense of well-being (coefficient - 1.10 [- 1.66, - 0.54]), but no association was detected for social isolation. CONCLUSIONS: When accounting for factors associated with underlying physical health status, self-reported dysphagia is independently associated with negative psychosocial health and warrants attention by healthcare providers. Future studies should aim to identify causal factors and the extent to which interventions may mitigate these factors.

Dysphagia in Older Adults is Associated With Food Insecurity and Being Homebound.

Objective: Our aim was to evaluate relationships between swallowing difficulty (dysphagia) and social determinants of health (SDOH) in older adults ≥65 years. Method: Cross-sectional analyses were performed in community-dwelling Medicare beneficiaries from the National Health & Aging Trends Study (NHATS). The primary exposure was self-reported difficulty chewing/swallowing in the prior month. Dependent measures included a variety of SDOH outcomes (e.g., food insecurity [FI]). Weighted logistic regression models were estimated to determine associations between dysphagia and SDOH outcomes. Results: Of 4041 participants, 428 (10.6%) self-reported dysphagia. In the adjusted model, dysphagia was associated with significantly increased odds for FI (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.06, 2.07, p = .023) and being homebound (OR = 1.32, 95% CI = 1.13, 1.55, p= < .001). Discussion: Older adults with dysphagia had increased odds of FI and being homebound. These associations have implications for health-promoting interventions at the individual and policy levels in older adults.

Experimental Approaches for the Synthesis of Low-Valent Metal-Organic Frameworks from Multitopic Phosphine Linkers.

Metal-organic frameworks (MOFs) are the subject of intense research focus due to their potential applications in gas storage and separation, biomedicine, energy, and catalysis. Recently, low-valent MOFs (LVMOFs) have been explored for their potential use as heterogeneous catalysts, and multitopic phosphine linkers have been shown to be a useful building block for the formation of LVMOFs. However, the synthesis of LVMOFs using phosphine linkers requires conditions that are distinct from those in the majority of the MOF synthetic literature, including the exclusion of air and water and the use of unconventional modulators and solvents, making it somewhat more challenging to access these materials. This work serves as a general tutorial for the synthesis of LVMOFs with phosphine linkers, including information on the following: 1) the judicious choice of the metal precursor, modulator, and solvent; 2) the experimental procedures, air-free techniques, and required equipment; 3) the proper storage and handling of the resultant LVMOFs; and 4) useful characterization methods for these materials. The intention of this report is to lower the barrier to this new subfield of MOF research and facilitate advancements toward novel catalytic materials.