bluuebunny/crossref_metadata_2025 huggingface dataset:
Sulfatide imaging identifies tumor cells in colorectal cancer peritoneal metastases
Authors: Sarcinelli G. M. , Varinelli L. , Ghislanzoni S. , Padelli F. , Lorenzini D. , Vingiani A. , Milione M. , Guaglio M. , Kusamura S. , Deraco M. , Pruneri G. , Gariboldi M. , Baratti D. , Bongarzone I.
Published: June 2024

Even with systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), peritoneal metastases (PM) remain a common site of disease progression for colorectal cancer (CRC) and are frequently associated with a poor prognosis. The mass spectrometry (MS) method known as Matrix-Assisted Laser Desorption/Ionization – Time of Flight (MALDI-TOF) is frequently used in medicine to identify structural compounds and biomarkers. It has been demonstrated that lipids are crucial in mediating the aggressive growth of tumors. In order to investigate the lipid profiles, particularly with regard to histological distribution, we used MALDI-TOF MS (MALDI-MS) and MALDI-TOF imaging MS (MALDI-IMS) on patient-derived tumor organoids (PDOs) and PM clinical samples. According to the MALDI-IMS research shown here, the predominant lipid signature of PDOs in PM tissues, glycosphingolipid (GSL) sulfates or sulfatides, or STs, is unique to the areas containing tumor cells and absent from the surrounding stromal compartments. Bioactive lipids are derived from arachidonic acid (AA), and AA-containing phosphatidylinositol (PI), or PI (18:0–20:4), is shown to be highly expressed in the stromal components. On the other hand, the tumor components contained a higher abundance of PI species with shorter and more saturated acyl chains (C34 and C36 carbons). The cellular subversion of PI and ST species may alter in ways that promote the growth, aggressiveness, and metastasis of tumor cells. Together, these findings suggest that the GSL/ST metabolic programming of PM may contain novel therapeutic targets to impede or halt PM progression.
Obstructive sleep apnea: What is an orthodontist’s role?
Authors: Kazmierski Robert H.
Published: July 2024

Background

The American Association of Orthodontists white paper on obstructive sleep apnea and orthodontics remains the most authoritative statement on the topic. This was produced in 2019 due to increasing orthodontic interest in obstructive sleep apnea (OSA) and the lack of formal guidelines for orthodontists. Since the white paper’s release, advocacy for contrarian ideas and practices remain. Orthodontists are sometimes acting as primary care providers for OSA. Procedures appropriate only for screening are sometimes being used for diagnosis. The side effects of effective treatments such as mandibular advancement devices need further consideration. Also, research has clarified the effectiveness and ineffectiveness of treatments such as palatal expansion.

Results

Part of an orthodontist’s role is screening for OSA. The correct action when this is suspected remains referral to the appropriate physician specialist for diagnosis and treatment or coordination of treatment. Orthodontists may participate in the treatment of patients with OSA as a member of a multi-disciplinary team. Effective orthodontic treatments may include orthognathic surgery with maxillomandibular advancement and mandibular advancement devices. The negative effects of the latter make this a choice of last resort. Current research indicates that OSA alone is not sufficient indication for palatal expansion.

Conclusions

Orthodontists should appropriately screen for obstructive sleep apnea. This may be done as part of our health histories, our clinical examination, and review of radiographs taken for purposes other than the diagnosis and screening for OSA. Orthodontic treatment for OSA can be helpful and effective. However, this may be done only after referral to the appropriate physician specialist, as part of a multi-disciplinary team, with consideration of the likely effectiveness of treatment, and after all likely and potential negative consequences have been considered and thoroughly discussed with the patient.
Increased risk of developing cerebro-cardiovascular diseases in police officers: a nationwide retrospective cohort study
Authors: Ko Juyeon , Park Hyunji , Park Sungha , Kim Dae-hee , Cho Jaelim
Published: July 2024

Background

Police officers face an increased risk of developing cerebro-cardiovascular diseases (CVD). However, current literature lacks population-based cohort studies specifically focusing on this association. This study aimed to investigate the association between police officers and the risk of developing CVD compared with education officers, while accounting for socioeconomic and demographic factors.

Methods

We used the Korean National Health Insurance Service data spanning from 2009 to 2020. In this population-based retrospective matched cohort study, we identified age, sex, and calendar years of job-enrollment–matched education officers for each police officer. This study evaluated the CVD occurrence, including acute myocardial infarction, ischemic stroke, and hemorrhagic stroke. Using multivariable Cox regression analysis, we determined the risk of developing CVD, expressed as a hazard ratio (HR) and 95% confidence interval (CI).

Results

Among 104,134 police officers and 104,134 education officers, 4,391(42.2%) cases and 3,631(34.9%) cases of CVD occurred, respectively. The mean ± standard deviation age was 38.4 ± 9.4 years in police officers and 38.6 ± 9.5 years in education officers. The proportion of men was 84.8 % in both groups. Police officers were significantly associated with a higher risk of developing CVD compared with education officers, with an adjusted HR of 1.15 (95% CI, 1.09–1.22). In addition, police officers had significantly higher risks for acute myocardial infarction (adjusted HR, 1.16; 95% CI, 1.06–1.26) and ischemic stroke (adjusted HR, 1.17; 95% CI, 1.09–1.25).

Conclusions

The findings of our study highlight a significant increase in the risk of developing CVD among police officers, particularly among those aged 45 years and older and those with uncontrolled blood pressure compared to their education officer counterparts. Future cohort studies are required to confirm this association.
Regional changes in brain metabolism during the progression of mild cognitive impairment: a longitudinal study based on radiomics
Authors: Mu Xuxu , Cui Caozhe , Liao Jue , Wu Zhifang , Hu Lingzhi
Published: July 2024

Background

This study aimed to establish radiomics models based on positron emission tomography (PET) images to longitudinally predict transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD).

Methods

In our study, 278 MCI patients from the ADNI database were analyzed, where 60 transitioned to AD (pMCI) and 218 remained stable (sMCI) over 48 months. Patients were divided into a training set (n = 222) and a validation set (n = 56). We first employed voxel-based analysis of 18F-FDG PET images to identify brain regions that present significant SUV difference between pMCI and sMCI groups. Radiomic features were extracted from these regions, key features were selected, and predictive models were developed for individual and combined brain regions. The models' effectiveness was evaluated using metrics like AUC to determine the most accurate predictive model for MCI progression.

Results

Voxel-based analysis revealed four brain regions implicated in the progression from MCI to AD. These include ROI1 within the Temporal lobe, ROI2 and ROI3 in the Thalamus, and ROI4 in the Limbic system. Among the predictive models developed for these individual regions, the model utilizing ROI4 demonstrated superior predictive accuracy. In the training set, the AUC for the ROI4 model was 0.803 (95% CI 0.736, 0.865), and in the validation set, it achieved an AUC of 0.733 (95% CI 0.559, 0.893). Conversely, the model based on ROI3 showed the lowest performance, with an AUC of 0.75 (95% CI 0.685, 0.809). Notably, the comprehensive model encompassing all identified regions (ROI total) outperformed the single-region models, achieving an AUC of 0.884 (95% CI 0.845, 0.921) in the training set and 0.816 (95% CI 0.705, 0.909) in the validation set, indicating significantly enhanced predictive capability for MCI progression to AD.

Conclusion

Our findings underscore the Limbic system as the brain region most closely associated with the progression from MCI to AD. Importantly, our study demonstrates that a PET brain radiomics model encompassing multiple brain regions (ROI total) significantly outperforms models based on single brain regions. This comprehensive approach more accurately identifies MCI patients at high risk of progressing to AD, offering valuable insights for non-invasive diagnostics and facilitating early and timely interventions in clinical settings.
Cytokines in new-onset refractory status epilepticus: ready for clinical use?
Authors: Jin Zhenghan , Zhan Yixin , Chen Shijia , Zheng Yang
Published: July 2024

New-onset refractory status epilepticus (NORSE) is a rare and challenging condition characterized by refractory status epilepticus in an otherwise healthy patient without obvious causes. Increasing evidence suggests a change in cytokine profiles in NORSE. However, the clinical utility of cytokine testing remains uncertain, primarily because of the lack of robust study designs and limited sample sizes. A recent study published in Annals of Neurology investigated the cytokine profiles in both serum and cerebrospinal fluid samples of NORSE patients. The study found elevated levels of CXCL8, CCL2, and MIP-1α in the serum and elevated levels of IL-1ß in the cerebrospinal fluid of NORSE patients compared to those with other forms of refractory status epilepticus (RSE). Furthermore, patients with cryptogenic NORSE had even higher levels of CXCL8, CCL2, and MIP-1α in the serum. Patients with NORSE who exhibited elevated levels of innate immunity cytokines in the serum had worse outcomes at discharge and several months after the NORSE ended. In summary, these findings highlight the association between inflammation-related cytokines and NORSE, providing new insights into clinical diagnosis and treatment approaches.
Irinotecan plus anlotinib or further in combination with penpulimab as second-line treatment of metastatic colorectal cancer (ZL-IRIAN).
Authors: Wang Chenchen , Li Wenhua , Zhu Xiaodong , Geng Qirong , Zhao Xiaoying , Guo Weijian
Published: June 2024

3570

Background: The irinotecan based chemotherapy in combination with bevacizumab had become the standard second-line treatment for metastatic colorectal cancer (mCRC), but the efficacy was limited. Anlotinib, an oral anti-angiogenic tyrosine kinase inhibitor, had initially shown promising clinical effects when combined with chemotherapy in the first-line treatment of mCRC. Whether anlotinib could bring clinical benefit in the second line treatment warrants further exploration. The PD-1 antibody might have partial effects when combined with anti-angiogenic agents with or without chemotherapy in first- and third-line treatment for proficient mismatch repair (pMMR)/ microsatellite stable (MSS) mCRC. Our study was to explore the rationality of anlotinib plus chemotherapy or further combined with a novel anti-PD-1 IgG1 antibody—penpulimab in the second line treatment of mCRC. Methods: This study was an open label, non-randomized, multi-cohorts, phase II prospective clinical trial that included pts with pMMR/MSS mCRC who were eligible for the second-line systemic treatment. Two cohorts were established as follows: Cohort A consisted of anlotinib(10mg daily, d1-10, q2w) + irinotecan (180mg/m2 d6, q2w) (n=23); Cohort B consisted of anlotinib (8mg daily, d1-10, q2w)+irinotecan (180mg/m2 d6, q2w) + penpulimab (200mg, d6, q2w) (n=23). Pts were initially enrolled in Cohort A. If the ORR in Cohort A was ≥15% (at least four patients in Cohort A reached CR/PR), the enrollment of Cohort B started. The primary endpoint was ORR. Secondary endpoints included progress free survival (PFS), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. Results: A total of 23 Pts were enrolled in A cohort from March 9 2022 to December 3 2023. With an ORR of 39.1% (9/23) and DCR of 87.0% (20/22), the median PFS was 9.57 months (95% CI 5.24-13.90 months), and the 6-month and 12-month PFS rates were 70.9% and 38.2%, respectively. Pts in B cohort were enrolled from October 25 2022 to November 22 2023, a total of 23 pts were enrolled, 2 pts withdrew their informed consent before treatment and 21 pts received at least one dose of treatment. ORR of 21 pts was 42.9% (9/21), and the DCR was 90.5% (19/21). The median PFS had not reached, with the 6-month and 12-month PFS rates as 70.7% and 55%, respectively. Safety profile indicated that 65.2% (15/23) and 57.1% (12/21) experienced grade≥3 adverse events in A cohort and B cohort, respectively. Conclusions: The combination of anlotinib with irinotecan +/- PD-1 blockade in second-line treatment for mCRC had shown promising efficacy and good safety. Whether PD-1 blockade could bring extra survival benefits required longer follow-up. Clinical trial information: NCT05229003 .
Identification of prognostic genomic biomarkers in metastatic clear cell renal cell carcinoma (mccRCC): An analysis of the large retrospective real world clinico-genomic data from Flatiron Health (FH)-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB).
Authors: Rizzo Mimma , Pezzicoli Gaetano , Porta Camilla , Povero Massimiliano , Pradelli Lorenzo , Sicari Emilia , Barbiero Valentina Sara , Porta Camillo
Published: June 2024

4553

Background: Despite a number of therapeutic improvements, mccRCC still has a poor prognosis, with limited prognostic predictors for clinical practice. The aim of this study was to evaluate the prognostic value of three clusters of co-occurring genes in mccRCC. Methods: We conducted a retrospective analysis of adult patients with mccRCC who were profiled by performing FMI genomic tests using tissue biopsies or blood samples. Data were from the nationwide (US-based) de-identified FH-FMI CGDB, originating from approximately 280 US cancer clinics (~800 sites of care). Patients diagnosed from January 01, 2011 to June 30, 2022 were followed until death or the last available observation (within December 31, 2022). Overall Survival (OS) was estimated using the Kaplan-Meier methods, while Cox proportional hazard model with risk set adjustment was used to assess the prognostic role of three pre-specified clusters of co-occurring genes; cluster 1 (C1) included VHL, SETD2, PBRM1, KDM5C, MTOR, and NFE2L2, cluster 2 (C2) included TP53, TSC1, and TERT, while cluster 3 (C3) included CDKN2A, CDKN2B, BAP1, NF2, MTAP, and ARID1A. Patients were considered cluster-positive (+) if they exhibited mutations in at least one gene within the cluster, and none in the other clusters. Results: 789 mccRCC patients were included [median age: 61 years, male: 71.1%, white race: 71.2%]. Among the 720 (91.3%) treated patients, 516 (71.7%) and 59 (8.2%) were classified per IMDC score as poor/intermediate and favorable risk, respectively (145 missing). Overall, almost half (45.5%; 359) were profiled after the diagnosis of metastasis (median gap time of 7.9 months) and 29 (3.7%) underwent multiple profile assessments, resulting in a total of 818 specimens analyzed. 332 (42.1%), 27 (3.4%), and 32 (4.1%) patients were C1+, C2+, and C3+, respectively. Median OS was 37 months (95% CI: 34-42). C1+ patients had higher OS compared to C1- (median OS: 50 vs. 30 months; HR: 0.57, p<0.001), while C3+ was associated with worse OS (median OS: 38 vs. 20 months; HR: 1.94, p=0.004). No association was found between C2 and OS (HR: 1.27; p=0.4). C1+ patients were more frequently classified as favorable risk compared to C1- (10.2% C1+ vs. 6.8% C1-, p=0.046) and they had longer duration of first-line (L1) treatment (median DoT: 9 vs. 7 months, p = 0.02). No significant differences between C2+ and C2-, C3+ and C3- patients were observed in L1 duration and IMDC distribution. Conclusions: This large-scale study identified two independent prognostic gene clusters in mccRCC. Further analyses will focus on the validation of the predictive role of these biomarkers with the ultimate aim of helping us develop tailored treatment strategies.
Association of immune-related adverse events, inflammatory biomarkers, and clinical outcomes in patients treated with ICIs for advanced renal cell carcinoma.
Authors: Yildirim Ahmet , Wei Mengting , Liu Yuan , Goswamy Rohit Vivek , Choi Yujin , Brown Jacqueline T , Nazha Bassel , Martini Dylan J. , Hartman Caitlin , McClintock Greta Russler , Zhuang Tony , Kissick Haydn , Harris Wayne B. , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: June 2024

4556

Background: Immune Checkpoint Inhibitors (ICIs) have been the mainstay treatment for advanced renal cell carcinoma (aRCC). However, irAEs are still a challenge in clinical practice. We tested irAEs with inflammatory biomarkers and their association with clinical outcomes. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 2018 and 2023. irAEs determined by the primary oncologist and reported by CTCAE v5.0. Univariate and multivariate analyses were conducted to determine the association between race, gender, OS, PFS, clinical benefit (CB, stable disease, partial response, complete response), modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), neutrophil to eosinophil ratio (NER), and any grade irAE. MVA was built by controlling gender, race, smoking status, and prior treatment. Results: We analyzed 401 patients; 191 (47.6%) patients experienced any grade irAEs, with 41 (21.5%) of those classified as grade 3 or higher. Of 401 patients, 139 (34.6%) were treated with PD-1 inhibitor (PD-1i) monotherapy, 131 (32.6%) with PD-1i and CTLA-4 inhibitor combination, 108 (26.9%) with PD-1i and tyrosine kinase inhibitor combination. The median follow-up time was 43.0 months (36.5-51.3). On univariate analysis, the incidence of irAEs was higher in females than males (Odds ratio (OR),1.66 (1.08-2.57), p=0.021), White patients had a higher incidence of irAEs compared to African American patients (OR 2.20 (1.32-3.66), p=0.009). On multivariate analysis, low mGPS was correlated with a higher risk of irAEs (OR for mGPS of 0-1-2 was 6.03 (2.07-17.62), 3.75 (1.31-10.70), and reference respectively; p=0.004). irAEs were correlated with greater CB (OR 2.56 (1.53-4.29); p <.001), longer OS (HR 0.55 (0.37-0.82); p=0.003), and longer PFS (HR 0.51 (0.37-0.71); p <.001). Conclusions: Female patients, White patients, and patients with low inflammatory biomarkers may have a higher likelihood of experiencing irAEs. Patients who experienced irAEs may have better outcomes. Future prospective trials are needed for further evidence. [Table: see text]
Disparities in trends in bladder cancer mortality between urban and rural patients: A 2000-2020 analysis.
Authors: Al Armashi Abdul Rahman , Thierheimer Marisa , Bukavina Laura , Calaway Adam C. , Vince Randy , Mendiratta Prateek , Garcia Jorge A. , Brown Jason R
Published: June 2024

4583

Background: Patients in rural areas in the US often have worse healthcare outcomes due to socioeconomic deprivation, higher rates of smoking, and limited access to medical care. Despite a general decline in bladder cancer mortality over the past two decades, comprehensive studies comparing these trends between urban and rural mortality are scarce. Methods: Utilizing the CDC WONDER database, we extracted mortality data for bladder cancer from 2000 to 2020. Age-adjusted mortality rates per 100,000 persons were standardized to the Year 2000 US standard population. Data segmentation by urbanity utilized the 2013 National Center for Health Statistics Urban-Rural Classification Scheme. The National Cancer Institute's Joinpoint Regression Program was employed to calculate average annual percent changes (AAPCs) and annual percent changes (APCs). Results: In our analysis, we identified a total of 306,750 bladder cancer death cases from 2000 to 2020. Significant improvements in bladder cancer mortality were observed in urban areas, with large central metros experiencing the most pronounced decrease (AAPC -1.0%, p<0.001). This decline was moderate between 2000 and 2016 (APC -0.3, p< 0.001) but accelerated between 2016 and 2020 (APC -3.8%, p<0.001). Large fringe and medium metros also saw comparatively smaller but significant declines (AAPC -0.6%, P<0.05) and also accelerated between 2016-2020. In contrast, small metro and rural areas (micropolitan and noncore) showed no significant improvement, with mortality rates remaining stable between 2000 and 2020 (AAPC 0.2%, P=0.099). Conclusions: This analysis, the largest to date comparing urban and rural mortality trends in bladder cancer, highlights significant disparities in outcomes between large urban and rural areas. The marked improvement in urban areas, especially noted around the time novel agents such as immunotherapy were introduced, underscores the potential impact of advanced treatments. However, the stable mortality rates in rural areas suggest that access to advanced care, environmental influences, socioeconomic status, and slower adaptation of new guidelines in rural settings may play critical roles. These findings underline the urgent need for strategies to close the urban-rural gap. [Table: see text]
Prognostic factors of relapse in surgically resected small cell neuroendocrine carcinomas of the urothelial tract (SCNEC-URO).
Authors: Moussa Mohammad Jad , Wilson Nathaniel R. , Xiao Lianchun , Tabet Georges C. , Gao Jianjun , Shah Amishi Yogesh , Corn Paul Gettys , Goswami Sangeeta , Msaouel Pavlos , Tannir Nizar M. , Lee Byron H. , Kamat Ashish M. , Adibi Mehrad , Dinney Colin P.N. , Hansel Donna E. , Guo Charles C. , Siefker-Radtke Arlene O. , Campbell Matthew T , Alhalabi Omar
Published: June 2024

4605

Background: SCNEC-URO are rare aggressive cancers with limited treatments. Although they frequently co-exist (60-70%) with urothelial carcinoma (UC) at diagnosis, most metastatic biopsies of relapsing patients (pts) show pure small cell (SC) morphology. There are major unmet needs to predict relapse after definitive surgery. Methods: Data was extracted from a historical cohort of n=216 pts with surgery for surgically resectable disease (cT1-T4, N0 or N+, M0) at MD Anderson between November 1985 and June 2021. Morphology at resection was defined as: ‘pCR’ (pathological complete response, including no residual carcinoma or carcinoma in situ), ‘Any SCNEC’ (persistence of SC with UC in sample) or ‘Non-SCNEC’ (UC only). Relapse events after surgery were analyzed as time-to-event (TTE) outcome with competing risk non-parametric method. Univariable and multivariable analyses identified prognostic factors of relapse. Results: In TTE analysis, cohort events (n=216) included: n=70 censored (alive and relapse-free), n=92 failure events (with relapse), and n=54 competing events (death without known relapse). n=154 (71.3%) received neoadjuvant chemotherapy, including SCNEC regimens in 125/154 (81.2%) and UC regimens in 16/154 (10.4%). The 5-year cumulative incidence function (CIF) of relapse for all pts was 41.92% [95% CI: 35.2% - 48.5%]. CIF rates were significantly different per morphology at resection (Gray’s test, p<.0001). Pts with pCR had the lowest 5-year CIF rate for relapse (18.5%) [11.1% - 27.4%], while pts with ‘Any SCNEC’ had the highest CIF (69.6%) [58.6% - 78.9%]. Pts with Non-SCNEC had an intermediate CIF risk (31.6%) [17.6% - 46.7%]. Staging at resection also showed different CIF rates (Gray’s test, p<.0001). Pts with pT0N0 had the lowest CIF rate (12.8%) [5.6% - 23.2%], with CIF rates increasing with higher staging: pTisN0 (25%) [11.6% - 41%]; pT1N0 (25%) [5.4% - 51.7%]; pT2 or greater, but N0 (52.4%) [41% - 62.7%]. Pts staged node-positive (pN+) did not have an estimated 5-year CIF as most died within 5 years. In multivariable analysis, clinical staging at diagnosis, pathological staging and cellular morphology at resection were associated with relapse (Table). Conclusions: Besides staging at diagnosis and surgery, morphology at resection is a key predictor of relapse. Persistence of the SC component predicts a higher chance of relapse than its eradication and persistence of the UC component. While adjuvant therapy in UC has made significant progress recently, a tailored adjuvant approach addressing the residual SC component at definitive surgery is needed to improve outcomes and decrease relapse. [Table: see text]
Survival outcomes and subgroup analyses derived from a phase III randomized trial comparing afatinib to chemotherapy in treatment-naïve non-small cell lung cancer with a sensitizing uncommon epidermal growth factor receptor mutation (ACHILLES/TORG1834).
Authors: Sato Yuki , Miura Satoru , Misumi Toshihiro , Yoshioka Hiroshige , Tokito Takaaki , Fukuhara Tatsuro , Yamaguchi Ou , Yokoyama Toshihide , Kuyama Shoichi , Kurata Takayasu , Kato Terufumi , Horinouchi Hidehito , Takiguchi Yuichi , Goto Yasuhiro , Tanaka Kentaro , Mori Masahide , Ikeda Satoshi , Ichihara Eiki , Tanaka Hiroshi , Okamoto Hiroaki
Published: June 2024

8588

Background: The ACHILLES/TORG1834 trial is the first randomized phase 3 study, demonstrating the superiority of afatinib to chemotherapy in terms of progression-free survival (PFS) as a primary endpoint in sensitizing uncommon epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (the hazard ratio [HR] of PFS was 0.422, p=0.0007). This trial was early terminated due to efficacy according to the recommendation by the data and safety monitoring committee. Here we report the overall survival (OS) result, subgroup analysis of PFS, and the response data according to detailed mutation status at the primary analysis. Methods: In this open-label phase III study, treatment-naïve patients (n=109) with sensitizing uncommon EGFR mutant NSCLC were randomized 2:1 to oral afatinib (30 mg or 40 mg daily) or the combination of platinum (cisplatin 75 mg/m2 or carboplatin AUC 5 or 6) and pemetrexed (500 mg/m2), followed by pemetrexed maintenance therapy every 3 weeks. The primary endpoint was PFS per RECIST 1.1. The secondary endpoints included objective response rate (ORR), time to treatment failure (TTF), and OS. Results: Median follow-up time was 12.5 (range, 0 to 43.5) months. The OS HR of afatinib compared to chemotherapy was 0.989 (95% confidence interval [CI], 0.457 to 2.141; p=0.9772; 29/109 events, 26.6% maturity). Median OS was not reached in either population. All subgroups of PFS did better in the afatinib arm. In the subgroup regarding the starting dose of afatinib, the PFS HR in the 40mg afatinib arm (HR 0.128, 95%CI, 0.050 to 0.327) were favorable compared to that in the 30mg afatinib arm (HR 0.704, 95%CI, 0.352 to 1.406). In this subgroup, there were several differences in the baseline characteristics regarding age and gender. The detail of ORR and PFS according to mutations status was shown in the table. The safety profiles in both arms were consistent compared to previous reports. Conclusions: A consistent PFS benefit of afatinib over platinum-doublet chemotherapy was shown regardless the mutation status in patients with uncommon or compound EGFR mutations. The OS data were immature, and further follow-up will be warranted. Clinical trial information: 031180175. [Table: see text]
Survival differences in advanced non-small cell lung cancer after developments in regimens with immune check point inhibitors: Population based retrospective study from United States SEER database.
Authors: Kshetree Binay , Bhandari Supradepti
Published: June 2024

e20516

Background: Metastatic non-small cell lung cancers (NSCLC) are being treated with immune checkpoint inhibitors (ICI). Nivolumab was approved in 2015, pembrolizumab (pz) /atezolizumab (az) in 2016, pz-chemotherapy (Ch) (pemetrexed + carboplatin) in 2017; durvalumab, pz-Ch (paclitaxel) and az-Ch (bevacizumab, carboplatin, paclitaxel) in 2018. We aim to study population based overall survival (OS) differences before and after these approval. Methods: We used Surveillance, Epidemiology and End Results (SEER) research plus database (Nov 2022 submission,17 registries). Patients aged ≥ 20 years with NSCLC as “distant” (combined summary stage) from 2013-2018 were included. Time was stratified as Pre-ICI from 2013-2014, initial single agent ICI from 2015-2016 (ICI) and new ICI/ICI-Ch from 2017-2018 (n/ICICh). OS in these time periods was calculated using Kaplan Meier (KM) method and were compared with log rank tests. Multivariate analysis was done using cox proportional hazard ratios. p < 0.05 was considered for statistical significance. IBM SPSS was used for analysis. Results: Total of 6375 patients had advanced NSCLC from 2013-2018. 4 and 5-year survival from 2017-2018 was not available due to data up to 2020. The survival difference among three timelines was statistically significant (log rank test, χ2 = 20.795, p < 0.001). On multivariate analysis, ICI and n/ICICh had significantly lower risk of dying as in table compared to Pre-ICI. Male, age ≥50 years, Black/Asian/Pacific Islanders were at higher risk and who received radiotherapy/chemotherapy had a lower risk of dying. There was no significant difference among Hispanic versus non-Hispanic and among marital status. Conclusions: ICI shows clear survival benefits in advanced NSCLC in this population-based study which supports clinical trials. Racial, gender and older age disparities shown in this study will further help in guiding appropriate measures. Future analysis with new ICI/Ch therapy with new timelines will help show population-based survival benefits after updated database. [Table: see text]
Cortisol, Stress, and Disease—Bidirectional Associations; Role for Corticosteroid-Binding Globulin?
Authors: Lee Jessica H , Meyer Emily Jane , Nenke Marni Anne , Lightman Stafford L , Torpy David J
Published: June 2024

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent “primary stress system disorders” were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the “hypocortisolemic symptom triad” of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation–genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.
Perioperative Management of Massive Anterior Encephalocele in a Newborn: A Case Report
Authors: Ma Ricky , Brown Jason , Careskey Matthew
Published: July 2024

Anterior encephaloceles are rare neural tube defects posing anesthetic challenges. While anterior encephaloceles can cause airway obstruction at birth, this presentation is very rare and to our knowledge not reported in the literature. This case report describes a 34 weeks +0 days gestation, 2.6 kg, newborn with a massive nasoethmoidal anterior encephalocele creating significant external airway obstruction, necessitating emergent and thoughtful airway management and anesthetic care. Our most important perioperative considerations for this newborn included spontaneous ventilation using awake fiberoptic bronchoscopic intubation with lidocaine airway topicalization, secure endotracheal tube attachment, and avoiding noninvasive positive airway pressure postoperatively to avoid pneumocephalus.
Llgl1 mediates timely epicardial emergence and establishment of an apical laminin sheath around the trabeculating cardiac ventricle
Authors: Pollitt Eric J. G. , Sánchez-Posada Juliana , Snashall Corinna M. , Derrick Christopher J. , Noël Emily S.
Published: June 2024

During heart development, the embryonic ventricle becomes enveloped by the epicardium, which adheres to the outer apical surface of the heart. This is concomitant with onset of ventricular trabeculation, where a subset of cardiomyocytes lose apicobasal polarity and delaminate basally from the ventricular wall. Llgl1 regulates the formation of apical cell junctions and apicobasal polarity, and we investigated its role in ventricular wall maturation. We found that llgl1 mutant zebrafish embryos exhibit aberrant apical extrusion of ventricular cardiomyocytes. While investigating apical cardiomyocyte extrusion, we identified a basal-to-apical shift in laminin deposition from the internal to the external ventricular wall. We find that epicardial cells express several laminin subunits as they adhere to the ventricle, and that the epicardium is required for laminin deposition on the ventricular surface. In llgl1 mutants, timely establishment of the epicardial layer is disrupted due to delayed emergence of epicardial cells, resulting in delayed apical deposition of laminin on the ventricular surface. Together, our analyses reveal an unexpected role for Llgl1 in correct timing of epicardial development, supporting integrity of the ventricular myocardial wall.
Natural reversal of cavefish heart asymmetry is controlled by Sonic Hedgehog effects on the left-right organizer
Authors: Ng Mandy , Ma Li , Shi Janet , Jeffery William R.
Published: June 2024

The direction of left-right visceral asymmetry is conserved in vertebrates. Deviations of the standard asymmetric pattern are rare, and the underlying mechanisms are not understood. Here, we use the teleost Astyanax mexicanus, consisting of surface fish with normal left-oriented heart asymmetry and cavefish with high levels of reversed right-oriented heart asymmetry, to explore natural changes in asymmetry determination. We show that Sonic Hedgehog (Shh) signaling is increased at the posterior midline, Kupffer's vesicle (the teleost left-right organizer) is enlarged and contains longer cilia, and the number of dorsal forerunner cells is increased in cavefish. Furthermore, Shh increase in surface fish embryos induces asymmetric changes resembling the cavefish phenotype. Asymmetric expression of the Nodal antagonist Dand5 is equalized or reversed in cavefish, and Shh increase in surface fish mimics changes in cavefish dand5 asymmetry. Shh decrease reduces the level of right-oriented heart asymmetry in cavefish. Thus, naturally occurring modifications in cavefish heart asymmetry are controlled by the effects of Shh signaling on left-right organizer function.
The Hox code responsible for the patterning of the anterior vertebrae in zebrafish
Authors: Maeno Akiteru , Koita Rina , Nakazawa Hidemichi , Fujii Renka , Yamada Kazuya , Oikawa Sae , Tani Taisei , Ishizaka Mizuki , Satoh Koumi , Ishizu Atsuki , Sugawara Takumi , Adachi Urara , Kikuchi Morimichi , Iwanami Norimasa , Matsuda Masaru , Kawamura Akinori
Published: June 2024

The vertebral column is a characteristic structure of vertebrates. Genetic studies in mice have shown that Hox-mediated patterning plays a key role in specifying discrete anatomical regions of the vertebral column. Expression pattern analyses in several vertebrate embryos have provided correlative evidence that the anterior boundaries of Hox expression coincide with distinct anatomical vertebrae. However, because functional analyses have been limited to mice, it remains unclear which Hox genes actually function in vertebral patterning in other vertebrates. In this study, various zebrafish Hox mutants were generated for loss-of-function phenotypic analysis to functionally decipher the Hox code responsible for the zebrafish anterior vertebrae between the occipital and thoracic vertebrae. We found that Hox genes in HoxB- and HoxC-related clusters participate in regulating the morphology of the zebrafish anterior vertebrae. In addition, medaka hoxc6a was found to be responsible for anterior vertebral identity, as in zebrafish. Based on phenotypic similarities with Hoxc6 knockout mice, our results suggest that the Hox patterning system, including at least Hoxc6, may have been functionally established in the vertebral patterning of the common ancestor of ray-finned and lobe-finned fishes.
Asymmetric Reciprocity and the Cyclical Behavior of Wages, Effort, and Job Creation
Authors: Fongoni Marco
Published: June 2024

This paper develops a search and matching framework in which workers are characterized by asymmetric reference-dependent reciprocity and firms set wages by considering the effect that these can have on workers’ effort and, therefore, on output. The cyclical response of effort to wage changes can considerably amplify shocks, independently of the cyclicality of the hiring wage, which becomes irrelevant for unemployment volatility, and firms’ expectations of downward wage rigidity in existing jobs increases the volatility of job creation. The model is consistent with evidence on hiring and incumbents’ wage cyclicality, and provides novel predictions on the dynamics of effort. (JEL E24, E32, J23, J31, J41, J64)
Optimal Foreign Reserves and Central Bank Policy under Financial Stress
Authors: Céspedes Luis Felipe , Chang Roberto
Published: June 2024

We study foreign reserves accumulation and liquidity policy in an open economy under financial stress. Firms and households finance investment and consumption by borrowing from banks, which borrow from abroad. Binding financial constraints cause the domestic interest rate to rise over the world rate and the exchange rate to depreciate, implying inefficiently low investment and consumption. A role emerges for a central bank that accumulates reserves to provide international liquidity when financial frictions bind. Our analysis yields novel insights on the determinants of optimal reserves accumulation cum liquidity provision and their role vis-à-vis capital flow management policies. (JEL E21, E22, E43, E58, F31, F41)
Creation of a visually graphical quality management system of the Etalon enterprise in the aviation industry
Authors: Bantyukov Sergey
Published: June 2024

The article explores the already existing organizational quality monitoring system at the enterprise public Joint Stock Company AK Rubin. Rubin Aviation Corporation, in the condition of an increased need to provide aircraft with new and repair units, faced an increased load on production facilities. This article describes the main directions and types of activities of the enterprise, the organizational structure and quality management system of the PJSC AK Rubin enterprise, concludes that there is insufficient quality control at all stages of the product cycle, without a single program for monitoring and monitoring the production process. In this regard, the authors proposed and developed a program to improve the quality monitoring system in conditions of high workload. The applicability of this program was tested at the enterprise of the aviation industry of the Rubin Aviation Corporation. However, after testing the system, it became clear that the production cycle is quite pragmatic, but there are not big conflicts in the form of database polling. Thanks to the creation of the «Etalon» program at the enterprise for the quality control system, it simplified and made it possible to manage modules for controlling the technological process of producing high-quality products that will be created in the future to continue improving the quality of products manufactured by the aviation industry.
Simulation modeling of deformative indicators of departmental highways reinforced with a slag-silicate binder
Authors: Vikulin Igor' , Zinov'eva Vera , Nikul'cheva Oksana , Skrypnikov Aleksey , Sergeev A.
Published: June 2024

The article considers one of the ways to increase the strength of structural layers of departmental highways reinforced with a slag-licate binder. Based on the studied works devoted to this topic, it is concluded that the search for new materials used as binders is relevant, the solution of which will increase the volume of construction of departmental logging roads. The utilization of slags will increase the economic feasibility of building a public road for the enterprise, which will increase the profitability of the main production. Using correlative experimental data, a direct close correlation was established between the physical and chemical parameters of soils reinforced with a slag-silicate binder: compressive strength and tensile strength during bending; modulus of elasticity and modulus of deformation. Thus, when strengthening soils with a slag silicate binder, it is possible to obtain a material with a fairly wide range of strength and deformative parameters. It has been established that for soils reinforced with a slag-licate binder, it is necessary to establish an upper limit of compressive strength. Recommended strength parameters of slag silicate samples have been determined. As a result of the study, it was concluded that when strengthening soils with binders, it is necessary to take into account the composition and properties of soils, their ability to chemical and physico-chemical interaction with binders, as well as the composition and properties of binders introduced into soils and those processes of chemical and physico-chemical order that they flow between the soil and the binder, as well as in the binders themselves.
Modeling the occurrence of internal stresses in a complex material structure
Authors: Nikolenko S. , Kozodaev S. , Sazonova Svetlana
Published: June 2024

The article is devoted to solving the problem aimed at improving the operational characteristics of the bridge bed of a railway bridge through the use of dispersed reinforcement. It is noted that structural elements made of fibroconcrete behave similarly to reinforced concrete with increasing load: long before destruction, they experience a continuity violation. The question of the distribution of forces between the individual fibers that stop the crack, the change in these conditions during the destruction, the magnitude and directions of these efforts at the moment preceding the destruction is considered. A centrally stretched structural element chaotically reinforced with fibers with a violation of continuity in the form of a through crack perpendicular to the tensile stresses is investigated. The proposed dependencies allow us to estimate the distribution of forces between individual fibers crossing the crack and the deformations of the element associated with the opening of the latter, which is important for creating a unified methodology for calculating strength and determining deformations of fiber-reinforced concrete structures. The expediency of using dispersed (fiber) reinforcement in a ballast-free reinforced concrete slab is considered. The task statement and description of fiber reinforcement are completed. The subject area is proposed to be justified experimentally by studying fiber reinforced concrete for impact load and structures with dispersed reinforcement for alternating inertial load. The conducted experimental studies have shown the possibility of using dispersed (fiber) reinforcement in a ballast-free reinforced concrete slab.
Learning During the COVID-19 Pandemic and the Impact of Remote Instruction on Kindergarten Students: Teachers and Parents Tell All
Authors:   , Ndolo Sharon Ndinda
Published: June 2024

Over the past three years, there have been changes in learning observed due to COVID-19 pandemic-related disruptions that affected young learners who needed support during instruction, raising concerns about their learning progress. As such, this qualitative phenomenological study explored and described the parent and teacher perspectives on the long-lasting impact of COVID-19 on kindergarten students who started formal education virtually during a pandemic. The central research question, "What are the teacher and parent perspectives on learning during the pandemic and their views on the impact of remote instruction on kindergarteners?" was examined from a constructivist and play-based learning theory. The study used purposeful and snowball sampling to obtain five teachers and four parents who virtually completed one-on-one 15- to 30-minute semi-structured interviews. Data was analyzed using Boije's constant comparative approach using three steps: (1) comparison within a single interview, (2) comparison between interviews within the same group, and (3) comparison of interviews from the two different groups. I used an inductive approach using axial coding to interpret results on themes that surfaced from within the participants' interviews. The study findings will benefit educators, school leaders, policymakers, and researchers interested in early childhood education. Limitations of the study include lack of generalizability, exclusive focus on the kindergarten level of study, and the use of previous literature conducted in different contexts and cultures to support the need for the study.
Efficient Metal-Organic Emitters for OLED Applications: Photophysics, Molecular Stacking, and Device Engineering
Authors:   , Li Shan
Published: June 2024

This dissertation addresses the following issues. Firstly, to reduce the efficiency roll-off at high current densities or brightness, of green, fluorescent organic light-emitting (OLEDs), we introduced a double-doped structure into the emissive layer. It includes two thin buffer layers and a broad emissive region stacked with two doped layers. This modification better controls charge injection/transport and recombination, boosting EL and PL efficiency. Secondly, aiming for highly efficient phosphorescent OLEDs surpassing the theoretical EQE limit of ~20%, a new class of platinum(II)-based phosphorescent complexes have been designed and synthesized serving as both emitters and electron transporters in straightforward undoped bi-/tri-layered devices. Achieving this without costly doping techniques, these OLEDs boast a relatively low turn-on voltage, extremely high power efficiency, and stable emission color dependent on applied voltages. This design anticipates reduced or no efficiency roll-off even at brightness levels exceeding 20,000 cd/m2, far surpassing DOE technology requirements (only 500-1500 cd/m2). This work sheds light on the influence of molecular design on crystalline packing and optoelectronic device performance and accelerates the development of efficient and stable Pt-based emitters.