tbuckley/cabot-search huggingface dataset:
New and emerging treatments for major depressive disorder
Authors: Cecilia Njenga, Parashar Pravin Ramanuj, Frederico Jose Coelho de Magalhães, Harold Alan Pincus
Journal: BMJ (2024)

Abstract Major depressive disorder (MDD) affects a substantial portion of the population; however, much is still unknown about the pathophysiology of this disorder. Treatment resistance highlights the heterogeneous nature of MDD and the need for treatments to target more than monoamine neurotransmission. This review summarizes research into the new and emerging targets of MDD. These include drugs such as psychedelics, antibiotics, opioid modulators, neuropeptides, and onabotulinumtoxin. Neuromodulatory treatments such as light based therapies and neuromodulation involving either magnetic or electrical stimulation are also discussed. Almost all interventions, pharmacological and neuromodulation, were trialed as adjunctive treatments to an antidepressant. Most research has been conducted on psychedelics, with trials suggesting rapid antidepressant and anti-suicidal effects. Trial findings, tolerability, study design limitations and quality of research have been considered throughout this review. There remains challenges in forming recommendations with the current research at present. With there being considerable interest into the research of new and emerging treatments—in particular, psychedelics—there may be scope in the future to form more robust recommendations.
Longitudinal analysis of the lung proteome reveals persistent repair months after mild to moderate COVID-19
Authors: Shreya M. Kanth, Julio A. Huapaya, Salina Gairhe, Honghui Wang, Xin Tian, Cumhur Y. Demirkale, Chunyan Hou, Junfeng Ma, Douglas B. Kuhns, Danielle L. Fink, Ashkan Malayeri, Evrim Turkbey, Stephanie A. Harmon, Marcus Y. Chen, David Regenold, Nicolas F. Lynch, Sabrina Ramelli, Willy Li, Janell Krack, Janaki Kuruppu, Michail S. Lionakis, Jeffrey R. Strich, Richard Davey, Richard Childs, Daniel S. Chertow, Joseph A. Kovacs, Parizad Torabi- Parizi, Anthony F. Suffredini, Gloria Pastor, Doris Swaim, Seynt Jiro Sahagun, Julia Purdy, Cheryl Chairez, Nicola Dee, Kara Curl, Catherine Rehm, Ulisses Santamaria, Rocco Caldararo, Sara Alsaaty
Journal: Cell Reports Medicine (2024)

In order to assess homeostatic mechanisms in the lung after COVID-19, changes in the protein signature of bronchoalveolar lavage from 45 patients with mild to moderate disease at three phases (acute, recovery, and convalescent) are evaluated over a year. During the acute phase, inflamed and uninflamed phenotypes are characterized by the expression of tissue repair and host defense response molecules. With recovery, inflammatory and fibrogenic mediators decline and clinical symptoms abate. However, at 9 months, quantified radiographic abnormalities resolve in the majority of patients, and yet compared to healthy persons, all showed ongoing activation of cellular repair processes and depression of the renin-kallikrein-kinin, coagulation, and complement systems. This dissociation of prolonged reparative processes from symptom and radiographic resolution suggests that occult ongoing disruption of the lung proteome is underrecognized and may be relevant to recovery from other serious viral pneumonias.
Novel Therapies in Cancer: Trials and Tribulations
Authors: Saiama N. Waqar, Ramaswamy Govindan
Journal: Clinical Cancer Research (2024)

Clinical trials are the backbone for advancing therapeutic options for patients diagnosed with cancer. Yet only 7.1% of patients with cancer participate in clinical trials in the United States. In this article, we review some of the reasons for poor accrual and discuss potential solutions. See related article by van Berge Henegouwen et al., p. 3937.
A Genome‐Wide Association Study Suggests New Susceptibility Loci for Primary Antiphospholipid Syndrome
Authors: Desiré Casares‐Marfil, Manuel Martínez‐Bueno, Maria Orietta Borghi, Guillermo Pons‐Estel, Guillermo Reales, Yu Zuo, Gerard Espinosa, Timothy Radstake, Lucas L. van den Hoogen, Chris Wallace, Joel Guthridge, Judith A James, Ricard Cervera, Pier Luigi Meroni, Javier Martin, Jason S. Knight, Marta E. Alarcón‐Riquelme, Amr H. Sawalha
Journal: Arthritis & Rheumatology (2024)

Objective Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. Methods We performed a genome‐wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta‐analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune‐mediated diseases. Results We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA‐DRA and in STAT1‐STAT4 with a genome‐wide level of significance; 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele near HLA‐DRA is associated with overexpression of HLA‐DRB6 , HLA‐DRB9 , HLA‐DQA2 , and HLA‐DQB2 in immune cells, vascular tissue, and nervous tissue. This association is independent of the association between PAPS and HLA‐DRB1*1302 . Functional analyses highlighted immune‐related pathways in PAPS‐associated loci. The comparison with other immune‐mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren syndrome, suggesting co‐localized causal variations close to STAT1‐STAT4 , TNPO3 , and BLK . Conclusion This study represents a comprehensive large‐scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease. image
The efficacy of atezolizumab plus bevacizumab in the treatment of unresectable hepatocellular carcinoma in cirrhotic and non-cirrhotic patients.
Authors: Alejandro Aranda-Gutierrez, Emilio Conde-Flores, Andres Meraz-Brenez, Salvador Escorza, Mónica I. Isabel Meneses-Medina, Fidel David Huitzil-Melendez, Héctor de la Mora-Molina, Vanessa Rosas Camargo
Journal: Journal of Clinical Oncology (2024)

e16214 Background: The IMbrave150 trial established that the combination of atezolizumab plus bevacizumab (AB) confers a significant progression-free survival (PFS) benefit when compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). However, the nuanced impact of cirrhotic status on treatment response was not established by the study, leaving a critical aspect of patient stratification and outcomes yet to be fully understood. Methods: We conducted a retrospective single-center study of patients with HCC treated with AB between 2020 and 2023. Eligible patients were those who underwent at least one cycle of AB and had a follow-up period of at least three months post-AB initiation. Independent samples T-test and X 2 and Fisher’s exact tests were used to evaluate associations between variables. PFS was calculated using the Kaplan-Meier method and compared according to cirrhotic status using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results: Among 28 patients, the mean age at diagnosis was 64 years (SD 11), 18 (64%) were male, 26 (93%) had Child-Pugh (CP) class A liver function, and 18 (64%) were cirrhotic. Most patients presented with Barcelona Clinic Liver Cancer stage C disease (61%) and received AB in the first-line setting (93%). Clinicopathological features according to cirrhotic status are detailed in Table 1. With a median follow-up of 14 months (95% CI 8-20) since AB initiation, 16 progression events were recorded, resulting in a median PFS of 12 months (95%CI 6-18) for the entire cohort. Univariate analysis revealed an inferior median PFS in patients with cirrhotic HCC (7 months [95%CI 5-9] vs. not reached [p = 0.038]). However, in a multivariate Cox analysis, only obesity emerged as a significant predictor of an inferior PFS (HR 4.6; 95% CI 1.3 - 16.0, p = 0.018). Conclusions: In our study, cirrhosis was not associated with an inferior PFS. Notably, the majority of cirrhotic patients in this cohort exhibited CP A liver function, so uncertainties persist regarding the impact of cirrhosis on cancer progression in patients with CP B and C liver function. Further investigation is warranted to comprehensively evaluate whether cirrhotic, non-cirrhotic, and obese subgroups respond differently to AB therapy. [Table: see text]
Evidence From the USPSTF and New Approaches to Evaluate Interventions to Prevent Child Maltreatment
Authors: Laura C. Hart, Meera Viswanathan, Wanda K. Nicholson, Michael Silverstein, James Stevermer, Sheena Harris, Rania Ali, Roger Chou, Emma Doran, Kesha Hudson, Caroline Rains, Nila Sathe, Adam J. Zolotor
Journal: JAMA Network Open (2024)

Importance The United States Preventive Services Task Force (USPSTF) has considered the topic of prevention of child maltreatment multiple times over its nearly 40-year history, each time reaching the conclusion that the evidence is insufficient to recommend for or against interventions aimed at preventing this important health problem with significant negative sequelae before it occurs. In the most recent evidence review, which was conducted from August 2021 to November 2023 and published in March 2024, the USPSTF considered contextual questions on the evidence for bias in reporting and diagnosis of maltreatment in addition to key questions regarding effectiveness of interventions to prevent child maltreatment. Observations A comprehensive literature review found evidence of inaccuracies in risk assessment and racial and ethnic bias in the reporting of child maltreatment and in the evaluation of injuries concerning for maltreatment, such as skull fractures. When children are incorrectly identified as being maltreated, harms, such as unnecessary family separation, may occur. Conversely, when children who are being maltreated are missed, harms, such as ongoing injury to the child, continue. Interventions focusing primarily on preventing child maltreatment did not demonstrate consistent benefit or information was insufficient. Additionally, the interventions may expose children to the risk of harm as a result of these inaccuracies and biases in reporting and evaluation. These inaccuracies and biases also complicate assessment of the evidence for making clinical prevention guidelines. Conclusions and Relevance There are several potential strategies for consideration in future efforts to evaluate interventions aimed at the prevention of child maltreatment while minimizing the risk of exposing children to known biases in reporting and diagnosis. Promising strategies to explore might include a broader array of outcome measures for addressing child well-being, using population-level metrics for child maltreatment, and assessments of policy-level interventions aimed at improving child and family well-being. These future considerations for research in addressing child maltreatment complement the USPSTF’s research considerations on this topic. Both can serve as guides to researchers seeking to study the ways in which we can help all children thrive.
Nonadjuvanted Bivalent Respiratory Syncytial Virus Vaccination and Perinatal Outcomes
Authors: Moeun Son, Laura E. Riley, Anna P. Staniczenko, Julia Cron, Steven Yen, Charlene Thomas, Evan Sholle, Lauren M. Osborne, Heather S. Lipkind
Journal: JAMA Network Open (2024)

Importance A nonadjuvanted bivalent respiratory syncytial virus (RSV) prefusion F (RSVpreF [Pfizer]) protein subunit vaccine was newly approved and recommended for pregnant individuals at 32 0/7 to 36 6/7 weeks’ gestation during the 2023 to 2024 RSV season; however, clinical vaccine data are lacking. Objective To evaluate the association between prenatal RSV vaccination status and perinatal outcomes among patients who delivered during the vaccination season. Design, Setting, and Participants This retrospective observational cohort study was conducted at 2 New York City hospitals within 1 health care system among patients who gave birth to singleton gestations at 32 weeks’ gestation or later from September 22, 2023, to January 31, 2024. Exposure Prenatal RSV vaccination with the RSVpreF vaccine captured from the health system’s electronic health records. Main Outcome and Measures The primary outcome is preterm birth (PTB), defined as less than 37 weeks’ gestation. Secondary outcomes included hypertensive disorders of pregnancy (HDP), stillbirth, small-for–gestational age birth weight, neonatal intensive care unit (NICU) admission, neonatal respiratory distress with NICU admission, neonatal jaundice or hyperbilirubinemia, neonatal hypoglycemia, and neonatal sepsis. Logistic regression models were used to estimate odds ratios (ORs), and multivariable logistic regression models and time-dependent covariate Cox regression models were performed. Results Of 2973 pregnant individuals (median [IQR] age, 34.9 [32.4-37.7] years), 1026 (34.5%) received prenatal RSVpreF vaccination. Fifteen patients inappropriately received the vaccine at 37 weeks’ gestation or later and were included in the nonvaccinated group. During the study period, 60 patients who had evidence of prenatal vaccination (5.9%) experienced PTB vs 131 of those who did not (6.7%). Prenatal vaccination was not associated with an increased risk for PTB after adjusting for potential confounders (adjusted OR, 0.87; 95% CI, 0.62-1.20) and addressing immortal time bias (hazard ratio [HR], 0.93; 95% CI, 0.64-1.34). There were no significant differences in pregnancy and neonatal outcomes based on vaccination status in the logistic regression models, but an increased risk of HDP in the time-dependent model was seen (HR, 1.43; 95% CI, 1.16-1.77). Conclusions and Relevance In this cohort study of pregnant individuals who delivered at 32 weeks’ gestation or later, the RSVpreF vaccine was not associated with an increased risk of PTB and perinatal outcomes. These data support the safety of prenatal RSVpreF vaccination, but further investigation into the risk of HDP is warranted.
Patients with metastatic cholangiocarcinoma in Italy and their healthcare resource consumptions and related costs.
Authors: Immacolata Esposito, Giulia Ronconi, Letizia Dondi, Silvia Calabria, Carlo Piccinni, Leonardo Dondi, Irene Dell'anno, Alice Addesi, Nello Martini
Journal: Journal of Clinical Oncology (2024)

e16139 Background: Patients with cholangiocarcinoma (CCA) are often diagnosed at late-stage disease. Few or any therapeutic options are possible for older patients with metastases (mCCA) and comorbidities. This analysis aimed to identify and characterize newly mCCA diagnosed patients in Italy in terms of clinical features, healthcare resource consumptions and related costs charged to the Italian National Health Service (SSN). Methods: From the Fondazione ReS (Ricerca e Salute) database (~5 million inhabitants/year), among adults with primary/secondary in-hospital diagnosis of CCA in 2018 and analysable look-back period until 2013, patients newly diagnosed with lymph nodes/distant metastases (index date) were selected. They were characterized by age, sex, and comorbidities (cardiometabolic, respiratory and cerebrovascular disorders, depression, chronic kidney disease and inflammatory bowel diseases). Rate of antineoplastic treatment dispensations and hepatic metastasectomy, overall and progression-free survivals - through Kaplan-Meier curves - among patients treated (vs untreated), and healthcare costs charged to the SSN were assessed during 2 years following index date. Results: In 2018, 176 newly mCCA diagnosed patients (incidence: 4.4x100,000 adult inhabitants; 31% of CCA patients) were identified. Males were 52.3%. Mean age was 72±10 years, and 65% of patients had ≥2 comorbidities. During 1 year following index date, 45.5% of newly mCCA diagnosed patients underwent antineoplastic treatment and/or surgery (mean age was 69±9 years), of whom, 61% were males, 67% had ≥2 comorbidities. During 2 years following index date: 34 patients were lost from 1 st to 2 nd year; 77% of treated patients died (vs 93.8% untreated; p &lt; 0.01); 87.5% of treated patients relapsed, on average after 6.3 months following index date. On average, during 1 st and 2 nd follow-up year, respectively: each mCCA patient weighed on the SSN € 12,699 and € 8,298; hospitalizations accounted 87% and 78% of the respective total expenditure. From 1 st to 2 nd follow-up year, respectively, the expenditure for hospitalizations and pharmaceuticals decreased from € 11,017 to € 6,498 and from € 700 to € 590, while costs for local outpatient services increased from € 982 to € 1,210. Conclusions: This study suggests that newly mCCA diagnosed patients strongly impact on the SSN, and that antineoplastic treatments and/or surgery, if applicable, can reduce mortality with substantial survival benefit.
Preclinical antitumor efficacy of ETN101, a novel oral anticancer agent with Wnt/ß-catenin signaling inhibition, TME modulation, and VEGFR2 targeting for advanced hepatocellular carcinoma treatment.
Authors: HyeJin Yang, Yeoun-Hee Kim, Garam Choi, Hyun Jin Park, Yesl Kim, Min-Jin Choi, Eunbee Jang, Sang Heon Jo, Sarah Kim, Seonghwan Hwang, Tae-Jun Kwon, Dongkyu Kim
Journal: Journal of Clinical Oncology (2024)

e16138 Background: Hepatocellular carcinoma (HCC) is an important cancer in worldwide with over 900,000 new cases and approximately 830,000 deaths were reported in 2020. It ranks sixth in global cancer incidence and third in mortality, highlighting its worldwide significance. The high frequency of occurrence and elevated mortality rates contribute to a significant socio-economic burden. However, most patients are diagnosed in the middle and late stages, missing the optimal treatment. Therefore, it is necessary to develop novel, safe, and effective drugs for HCC inhibition, elucidating their mechanisms of action. Methods: Evaluation of ETN101 was utilized in subcutaneous xenograft and orthotopic animal models with human HCC cell lines. ETN101 was administered orally. The tumor volume, tumor weight, and bodyweight were measured, and cancer cell proliferation and apoptosis were also analyzed. The toxicity of ETN101 was investigated through GOT/GPT and histological analysis in the liver and kidney. The signaling mechanism of ETN101 was analyzed through kinase analysis, phosphorylation, in silico docking analysis, and RNA sequencing, both in vitro and in vivo. Results: ETN101 demonstrated approximately 30% tumor inhibition at 10 mg/kg group compared to control. Moreover, 20 mg/kg treatment group also showed significant tumor reduction in all individuals with one complete response (CR). Interestingly, all individuals exhibited CR from 40 to 82 mg/kg treatment groups. During the 10 administrations of Nexavar and Lenvatinib, individuals who showed proliferated tumors persistently were selected, followed by the administration of ETN101. All individuals exhibited either CR or significant reduction in tumor volume upon ETN101. After tracking complete responders for two months, there were no signs of tumor recurrence or metastasis. These results suggested that ETN101 has anticancer effect by regulating Wnt/ß-catenin pathway in tumor microenvironment (TME) with increasing the infiltration of cytotoxic T cells into the tumor. Furthermore, it targets VEGFR2, blocking angiogenesis-related signals to improve therapeutic effects in advanced HCC. Conclusions: Due to lack of effective single drugs for advanced HCC patients, combination therapy is used clinically. We developed ETN101, a monotherapy that targets VEGFR2 and modulates the TME with the same mechanism as the combination therapy. ETN101 also showed excellent efficacy in preclinical study and secured a broad safety margin relative to the effective dose. In addition, ETN101 was effective in those who are not responded to conventional targeted cancer therapies. It is anticipated that ETN101 could serve as a novel therapeutic strategy for advanced HCC patients.
Comparison of checkpoint inhibitor–based regimens as first-line therapy in advanced hepatocellular carcinoma: A Frequentist Network meta-analysis of randomized clinical trials.
Authors: Muhammad Ashar Ali, Wajeeha Aiman, Mukarram Jamat Ali, Muhammad Yasir Anwar, Hamid Salim Shaaban, Gunwant K. Guron, Michael Maroules
Journal: Journal of Clinical Oncology (2024)

e16136 Background: Multiple immune checkpoint inhibitor (ICI) based regimens have shown better responses and survival rates than previously used sorafenib/lenvatinib in advanced hepatocellular carcinoma (HCC). However, there was no direct comparison done among different ICI-based regimens. This network meta-analysis focuses on the efficacy of different ICI-based regimens in advanced HCC as first-line therapy. Methods: A comprehensive literature search was performed on PubMed, and Embase from the inception of data till 12/30/2023 with keywords for “Hepatocellular carcinoma” AND “Immune Checkpoint Inhibitors”. We screened 5120 articles and included 8 randomized clinical trials (RCTs, N = 5834). “R” software and netmeta package was used to conduct this network meta-analysis. Atezolizumab + cabozantinib was randomly chosen as the comparator group. Results: 2208 patients were treated with ICI-based two-drug regimens, 1102 patients were treated with ICI monotherapy, 1937 patients were treated with sorafenib, and 399 patients were treated with lenvatinib. Overall survival (OS) was 0.63 (0.43-0.93), 0.64 (0.43-0.98), and 0.69 (0.48-0.99) in favor of sintilimab + bevacizumab, atezolizumab + bevacizumab, and camrelizumab + rivoceranib, respectively, as compared to atezolizumab + cabozantinib. Progression free survival (PFS) was 0.83 (0.54-1.27), 0.89 (0.58-1.35), and 0.94 (0.61-1.45) in favor of camrelizumab + rivoceranib, sintilimab + bevacizumab, and atezolizumab + bevacizumab, respectively, as compared to atezolizumab + cabozentinib. Odds ratio of overall response rate (ORR) 2.03 (0.67-6.13), 1.7 (0.65-4.43), and 1.46 (0.58-3.67) in favor of sintilimab + bevacizumab, camrelizumab + rivoceranib, and tremlimumab + durvalumab, respectively, as compared to atezolizumab + cabozantinib. P-scores for each regimen are in Table. Conclusions: Among ICI combinations, better survival and response rates were reported with sintilimab + bevacizumab, atezolizumab + bevacizumab, and camrelizumab + rivoceranib. Therefore, these regimens should be preferred for treatment of advanced HCC as first line therapy in patients who can tolerate these regimens. [Table: see text]