bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salivary Interleukin-6 and C-Reactive Protein/Mean Platelet Volume Ratio in the Diagnosis of Late-Onset Neonatal Pneumonia
Authors: Omran Ahmed , Ali Yasmin , Abdalla Mohamed Osama , El-Sharkawy Sonya , Rezk Ahmed R. , Khashana Abdelmoneim 
Published: October 2021

Neonatal pneumonia is a serious respiratory infectious disease with a high rate of case fatality in developing countries. Salivary cytokines could serve as interesting noninvasive markers in the diagnosis of neonatal pneumonia. The aim was to assess the diagnostic role of salivary and serum interleukin-6 (IL-6), C-reactive protein/mean platelet volume (CRP/MPV) ratio, and the combination of these markers in the diagnosis of late-onset neonatal pneumonia in full-term neonates. Seventy full-term neonates, 35 with late-onset neonatal pneumonia and 35 controls, were enrolled in this prospective case-control study. Complete blood count (CBC), salivary and serum IL-6, and CRP concentrations were measured for all the study subjects. The sensitivity, specificity, positive predictive value, and negative predictive value of salivary IL-6, serum IL-6, and CRP/MPV ratio for the diagnosis of late-onset neonatal pneumonia were determined. At the cutoff point of >34 pg/ml, salivary IL-6 showed 82.86% sensitivity and 91.43% specificity. CRP/MPV ratio showed a sensitivity of 97.14% and specificity of 85.71% at a

cutoff

value
>
0.88

. The combination of salivary IL-6 and CRP/MPV ratio improved the sensitivity and specificity to 100%. The current study shows for the first time that both salivary IL-6 and CRP/MPV ratio are suitable markers for the diagnosis of late-onset neonatal pneumonia in full-term neonates.
Neoadjuvant In Situ Immunomodulation Enhances Systemic Antitumor Immunity against Highly Metastatic Tumors
Authors: Oba Takaaki , Kajihara Ryutaro , Yokoi Toshihiro , Repasky Elizabeth A. , Ito Fumito 
Published: October 2021

Abstract

Neoadjuvant immunotherapy, given before surgical resection, is a promising approach to develop systemic antitumor immunity for the treatment of high-risk resectable disease. Here, using syngeneic and orthotopic mouse models of triple-negative breast cancer, we have tested the hypothesis that generation of tumor-specific T-cell responses by induction and activation of tumor-residing Batf3-dependent conventional type 1 dendritic cells (cDC1) before resection improves control of distant metastatic disease and survival. Mice bearing highly metastatic orthotopic tumors were treated with a combinatorial in situ immunomodulation (ISIM) regimen comprised of intratumoral administration of Flt3L, local radiotherapy, and in situ TLR3/CD40 stimulations, followed by surgical resection. Neoadjuvant ISIM (neo-ISIM) generated tumor-specific CD8+ T cells that infiltrated into distant nonirradiated metastatic sites, which delayed the progression of lung metastases and improved survival after the resection of primary tumors. The efficacy of neo-ISIM was dependent on de novo adaptive T-cell immunity elicited by Batf3-dependent dendritic cells and was enhanced by increasing dose and fractionation of radiotherapy, and early surgical resection after the completion of neo-ISIM. Importantly, neo-ISIM synergized with programmed cell death protein-1 ligand-1 (PD-L1) blockade to improve control of distant metastases and prolong survival, while removal of tumor-draining lymph nodes abrogated the antimetastatic efficacy of neo-ISIM. Our findings illustrate the therapeutic potential of neoadjuvant multimodal intralesional therapy for the treatment of resectable tumors with high risk of relapse.

Significance:
Neoadjuvant induction and activation of cDC1s in primary tumors enhances systemic antitumor immunity, suppresses metastatic progression, improves survival, and synergizes with anti–PD-L1 therapy.
T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy
Authors: Haj-Shomaly Jozafina , Vorontsova Avital , Barenholz-Cohen Tamar , Levi-Galibov Oshrat , Devarasetty Mahesh , Timaner Michael , Raviv Ziv , Cooper Tim J. , Soker Shay , Hasson Peleg , Weihs Daphne , Scherz-Shouval Ruth , Shaked Yuval 
Published: October 2021

AbstractMetastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer.Significance:Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis.See related commentary by Kolonin and Woodward, p. 197
An Allogeneic Multiple Myeloma GM-CSF–Secreting Vaccine with Lenalidomide Induces Long-term Immunity and Durable Clinical Responses in Patients in Near Complete Remission
Authors: Biavati Luca , Huff Carol Ann , Ferguson Anna , Sidorski Amy , Stevens M. Amanda , Rudraraju Lakshmi , Zucchinetti Cristina , Ali Syed Abbas , Imus Philip , Gocke Christian B. , Gittelman Rachel M. , Johnson Sarah , Sanders Catherine , Vignali Marissa , Gandhi Anita , Ye Xiaobu , Noonan Kimberly A. , Borrello Ivan 
Published: October 2021

Abstract

Purpose:
This proof-of-principle clinical trial evaluated whether an allogeneic multiple myeloma GM-CSF–secreting vaccine (MM-GVAX) in combination with lenalidomide could deepen the clinical response in patients with multiple myeloma in sustained near complete remission (nCR).

Patients and Methods:
Fifteen patients on lenalidomide were treated with MM-GVAX and pneumococcal conjugate vaccine (PCV; Prevnar) at 1, 2, 3, and 6 months.

Results:
Eight patients (53.3%) achieved a true CR. With a median follow-up of 5 years, the median progression-free survival had not been reached, and the median overall survival was 7.8 years from enrollment. MM-GVAX induced clonal T-cell expansion and measurable cytokine responses that persisted up to 7 years in all patients. At baseline, a higher minimal residual disease was predictive of early relapse. After vaccination, a lack of both CD27−DNAM1−CD8+ T cells and antigen-presenting cells was associated with disease progression.

Conclusions:
MM-GVAX, along with lenalidomide, effectively primed durable immunity and resulted in long-term disease control, as suggested by the reappearance of a detectable, fluctuating M-spike without meeting the criteria for clinical relapse. For patients in a nCR, MM-GVAX administration was safe and resulted in prolonged clinical responses.
Real-World Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015–2020
Authors: Arondekar Bhakti , Duh Mei Sheng , Bhak Rachel H. , DerSarkissian Maral , Huynh Lynn , Wang Kelsey , Wojciehowski John , Wu Melody , Wornson Bryon , Niyazov Alexander , Demetri George D. 
Published: October 2021

Abstract
Real-world evidence (RWE) has garnered great interest to support registration of new therapies and label expansions by the United States Food and Drug Administration (FDA). Currently, practical insights on the design and analysis of regulatory-grade RWE are lacking. This study aimed to analyze attributes of real-world studies in FDA's decision-making and characteristics of full versus accelerated approvals through a systematic review of oncology product approvals. Oncology approvals from 2015 to 2020 were reviewed from FDA.gov. Applications were screened for inclusion of RWE, and variables related to regulatory designations of the application, pivotal clinical trial, and real-world studies were extracted. FDA feedback was reviewed to identify takeaways and best practices for adequate RWE. Among 133 original and 573 supplemental approvals for oncology, 11 and 2, respectively, included RWE; none predated 2017. All real-world studies were retrospective in nature; the most common data source was chart review, and the most common primary endpoint was overall response rate, as in the pivotal trial. The FDA critiqued the lack of the following: a prespecified study protocol, inclusion/exclusion criteria matching to the trial, comparability of endpoint definitions, methods to minimize confounding and address unmeasured confounding, and plans to handle missing data. All full (versus accelerated) approvals shared the following characteristics: high magnitude of efficacy in the pivotal trial; designations of orphan disease, breakthrough therapy, and priority review; and no advisory committee meeting held. This study found that findings from external control real-world studies complemented efficacy data from single-arm trials in successful oncology product approvals.
Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis
Authors: Chandler Christopher S. , Bell Meghan M. , Chung Sebastian K. , Veach Darren R. , Fung Edward K. , Punzalan Blesida , Burnes Vargas Daniela , Patel Mitesh , Xu Hong , Guo Hong-fen , Santich Brian H. , Zanzonico Pat B. , Monette Sébastien , Nash Garrett M. , Cercek Andrea , Jungbluth Achim , Pandit-Taskar Neeta , Cheung Nai Kong V. , Larson Steven M. , Cheal Sarah M. 
Published: October 2021

Abstract

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26–27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS &gt; 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic “cure”) at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42–52.5 days (P &lt; 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.
Anastrozole Regulates Fatty Acid Synthase in Breast Cancer
Authors: Cairns Junmei , Ingle James N. , Kalari Krishna R. , Goetz Matthew P. , Weinshilboum Richard M. , Gao Huanyao , Li Hu , Bari Mehrab Ghanat , Wang Liewei 
Published: October 2021

Abstract
Our previous matched case–control study of postmenopausal women with resected early-stage breast cancer revealed that only anastrozole, but not exemestane or letrozole, showed a significant association between the 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor α. The mechanisms of endocrine resistance are heterogenous and with the new mechanism of anastrozole, we have found that treatment of anastrozole maintains fatty acid synthase (FASN) protein level by limiting the ubiquitin-mediated FASN degradation, leading to increased breast cancer cell growth. Mechanistically, anastrozole decreases the guided entry of tail-anchored proteins factor 4 (GET4) expression, resulting in decreased BCL2-associated athanogene cochaperone 6 (BAG6) complex activity, which in turn, prevents RNF126-mediated degradation of FASN. Increased FASN protein level can induce a negative feedback loop mediated by the MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, but not in patients treated with exemestane or letrozole. Repressing FASN causes regression of breast cancer cell growth. The anastrozole-FASN signaling pathway is eminently targetable in endocrine-resistant breast cancer.
Predictors of Left Ventricular Outflow Tract Obstruction After Transcatheter Mitral Valve Replacement in Severe Mitral Annular Calcification: An Analysis of the Transcatheter Mitral Valve Replacement in Mitral Annular Calcification Global Registry
Authors: El Sabbagh Abdallah , Al-Hijji Mohammed , Wang Dee Dee , Eleid Mackram , Urena Marina , Himbert Dominique , Chakravarty Tarun , Holzhey David , Pershad Ashish , Fang H. Kenith , Nejjari Mohammed , Zahr Firas , Dvir Danny , Sardar Muhammad Rizwan , Cheema Asim N. , Alnasser Sami , Iyer Vijay , Kaddissi Georges , Webb John , Makkar Raj , Vahanian Alec , O’Neill William , Rihal Charanjit , Guerrero Mayra 
Published: October 2021

Background:
Several studies have evaluated preprocedural imaging predictors of left ventricular outflow tract obstruction (LVOTO) after transcatheter mitral valve replacement. The patient cohorts in these studies were heterogeneous and included patients with transcatheter mitral valve replacement in failed bioprostheses, annuloplasty rings, and severe mitral annular calcification (MAC). The goal of this study was to evaluate predictors of LVOTO specific to patients undergoing valve-in-MAC.

Methods:
This study included patients with severe MAC who underwent valve-in-MAC and had optimal quality preprocedural multidetector row computed tomography scans eligible for retrospective analysis. Baseline demographic, echocardiographic, and procedural data on these patients were collected. multidetector row computed tomography parameters were analyzed for association with LVOTO, defined as increase in mean LVOT gradient by ≥10 mm Hg with accompanying hemodynamic instability.

Results:

Seventy-one patients with optimal preprocedural computed tomography scans were included in this study (mean age, 72.5±13.5 years), 9 of which developed LVOTO (all female). Baseline mean LVOT area, neo-LVOT area (145.3 versus 270.9 mm
2
;
P
=0.006), indexed neo-LVOT area (90.1 versus 157.4;
P
=0.05), and virtual transcatheter heart valve to septum distance (3.1 versus 6.9 mm;
P
=0.002) were lower in the LVOTO group. Expected % LVOT area reduction was higher in the latter group (58.3 versus 42.7%;
P
=0.008). In the univariable analysis, the baseline mean LVOT area, neo-LVOT area, indexed neo-LVOT area, and valve to septum distance were all significantly associated with LVOTO.

Conclusions:
The systolic mean LVOT area, neo-LVOT area, indexed neo-LVOT, expected percentage LVOT area reduction, and the valve to septum distance were associated with LVOTO after valve-in-MAC.
Impact of Intravascular Ultrasound–Guided Optimal Stent Expansion on 3-Year Hard Clinical Outcomes
Authors: Lee Yong-Joon , Zhang Jun-Jie , Mintz Gary S. , Hong Sung-Jin , Ahn Chul-Min , Kim Jung-Sun , Kim Byeong-Keuk , Ko Young-Guk , Choi Donghoon , Jang Yangsoo , Kan Jing , Pan Tao , Gao Xiaofei , Ge Zhen , Chen Shao-Liang , Hong Myeong-Ki 
Published: October 2021

Background:
Although stent underexpansion on intravascular ultrasound (IVUS) has been a major predictor for adverse outcomes in previous studies, these studies have primarily focused on angiographic restenosis or repeat revascularization with short-term follow-up. This study sought to evaluate the long-term benefit of different criteria for IVUS-defined optimal stent expansion on hard clinical outcomes.

Methods:
From the pooled data of 2 randomized trials, IVUS-XPL (Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions) and ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in All-Comers Coronary Lesions) that compared IVUS- versus angiography-guided drug-eluting stent implantation, a total of 1254 patients with IVUS-guided drug-eluting stent implantation into 1484 long lesions (implanted stent length, ≥28 mm) were included. Different criteria for IVUS-defined optimal stent expansion based on minimum stent area (MSA) as an absolute measure or MSA relative to reference lumen area were applied and validated. The primary end point was composite of cardiac death, target lesion–related myocardial infarction, or stent thrombosis at 3 years.

Results:

The rate of the primary end point was lower in patients with optimal stent expansion versus those without optimal stent expansion according to 3 IVUS-defined optimal stent expansion criteria: MSA >5.5 mm
2
(0.5% versus 2.2%; hazard ratio, 0.21 [95% CI, 0.06–0.75];
P
=0.008), MSA >5.0 mm
2
(0.6% versus 2.6%; hazard ratio, 0.24 [95% CI, 0.09–0.68];
P
=0.003), and MSA/distal reference lumen area >90% (0.5% versus 2.4%; hazard ratio, 0.32 [95% CI, 0.12–0.88];
P
=0.019). Achieving other relative expansion criteria, MSA/distal reference lumen area >100% or 80% or MSA/average reference lumen area >90% or 80%, was not associated with a reduction in hard clinical events.

Conclusions:

In patients undergoing IVUS-guided drug-eluting stent implantation for long lesions, achieving optimal stent expansion of MSA >5.5 mm
2
, >5.0 mm
2
, or MSA/distal reference lumen area >90% was associated with improved long-term hard clinical outcomes.
Waist circumference, hip circumference, arm span, and waist-to-hip ratio high risk of polycystic ovarian syndrome
Authors: Mawaddatina Tazkia , Budihastuti Uki Retno , Rahayu Dwi 
Published: October 2021

Background and Aims Polycystic ovarian syndrome is a reproductive problem of women with high prevalence cases accompanied by obesity conditions. Obesity condition can be seen from the size of waist circumference, hip circumference, arm span, and waist-to-hip ratio. This study aims to find out the risk factors between waist circumference size, hip circumference, arm span, and waist-to-hip ratio with polycystic ovarian syndrome. Methods This research is an analytical observation using a case-control approach conducted at Sekar Fertility Clinic and Poly Obgyn Dr Moewardi General Hospital Surakarta. Subjects were 150 consisting of 75 polycystic ovarian syndrome women and 75 normal fertile women. Sampling techniques used in this study are purposive sampling, researchers doing anthropometric measurements in the form of waist circumference, hip circumference, arm span, and waist-to-hip ratio simultaneously. The results were analyzed using Statistic Product and Service Solution 25. Results The results of the study obtained waist circumference with polycystic ovarian syndrome ( b = 3.002; CI 95% = 3.41–123.5; p = 0.001), hip circumference ( b = −2.671; CI 95% = 0.01–0.37; p = 0.002), arm span ( b = 5.318; CI 95% = 32.23–129.58; p < 0.001) and waist-to-hip ratio ( b = 1.761; CI 95% = 1.02–33.01; p = 0.047). Conclusion Waist circumference size, hip circumference, arm span, and waist-to-hip ratio correlate to a high risk of polycystic ovarian syndrome. Arm span is more dominant as an indicator of high risk to polycystic ovarian syndrome compared to waist circumference, hip circumference, and waist-to-hip ratio.
Role of Microglia and Astrocytes in Spinal Cord Injury Induced Neuropathic Pain
Authors: Miranpuri Gurwattan S. , Bali Parul , Nguyen Justyn , Kim Jason J , Modgil Shweta , Mehra Priya , Buttar Seah , Brown Greta , Yutuc Noemi , Singh Harpreet , Wood Aleksandar , Singh Jagtar , Anand Akshay 
Published: October 2021

Background: Spinal cord injuries incite varying degrees of symptoms in patients, ranging from weakness and incoordination to paralysis. Common amongst spinal cord injury (SCI) patients, neuropathic pain (NP) is a debilitating medical condition. Unfortunately, there remain many clinical impediments in treating NP because there is a lack of understanding regarding the mechanisms behind SCI-induced NP (SCINP). Given that more than 450,000 people in the United States alone suffer from SCI, it is unsatisfactory that current treatments yield poor results in alleviating and treating NP. Summary: In this review, we briefly discussed the models of SCINP along with the mechanisms of NP progression. Further, current treatment modalities are herein explored for SCINP involving pharmacological interventions targeting glia cells and astrocytes. Key message: The studies presented in this review provide insight for new directions regarding SCINP alleviation. Given the severity and incapacitating effects of SCINP, it is imperative to study the pathways involved and find new therapeutic targets in coordination with stem cell research, and to develop a new gold-standard in SCINP treatment.
Race-Based Differences in the Utilization and Timing of Secondary Cleft Procedures in the United States
Authors: Peck Connor J. , Pourtaheri Navid , Parsaei Yassmin , Gowda Arvind U. , Yang Jenny , Lopez Joseph , Steinbacher Derek M. 
Published: October 2021

Objective: Secondary procedures optimize outcomes following cleft lip and palate (CL/P) repair. We analyzed the association between race and the utilization and timing of revisionary/secondary cleft surgeries in the United States. Primary CL/P repair, revisions, and secondary procedures—cleft rhinoplasty, speech surgery, and alveolar bone grafting (ABG)—performed from 2014–2018 were identified from the Pediatric National Surgical Quality Improvement Program (NSQIP) database. Utilization estimates were derived via univariable and multivariable logistic regression. A Kruskal-Wallis rank-sum test and multivariable linear regression were used to assess differences in timing for each procedure cohort. The primary outcome measures were the odds of a patient being a certain race/ethnicity, and the age at which patients of different race/ethnicity receive surgery. There were 23 780 procedures analyzed. After controlling for sex, diagnosis, and functional status, there were significant differences in utilization estimates across procedure groups. Primarily, utilization was lowest in patient who were Black for cleft rhinoplasty (OR = 0.70, P = .023), ABG (OR = 0.44, P < .001) and speech surgery (OR = 0.57, P = .012), and highest in patients who were Asian patients in all surgery cohorts (OR 2.05-4.43). Timing of surgery also varied by race, although differences were minimal. Conclusions Estimates of utilization and timing of secondary cleft procedures varied by race, particularly among patients who were Black (poor utilization) or Asian (high utilization). Further studies should identify the causes and implications of underutilized and/or delayed cleft care.