bluuebunny/crossref_metadata_2025 huggingface dataset:
FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB
Authors: Kim Mi-Jeong , Kim Ji Young , Shin Ji Hye , Kang Yeeun , Lee Ji Su , Son Juhee , Jeong Soo-Kyung , Kim Daesik , Kim Duk-Hwan , Chun Eunyoung , Lee Ki-Young
Published: June 2023

Background

Free fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed.

Methods

We analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed. For the functional analysis, we generated FFAR2-knockout (FFAR2KO) A549 and FFAR2KO H1299 human lung cancer cells and performed biochemical mechanistic studies and cancer progression assays, including migration, invasion, and colony-formation assays, in response to TLR stimulation.

Results

The clinical TCGA data showed a significant down-regulation of FFAR2, but not FFAR1, FFAR3, and FFAR4, in lung cancer, and a negative correlation with TLR2 and TLR3. Notably, GSEA showed significant enrichment in gene sets related to the cancer module, the innate signaling pathway, and the cytokine-chemokine signaling pathway in FFAR2DownTLR2UpTLR3Up lung tumor tissues (LTTs) vs. FFAR2upTLR2DownTLR3Down LTTs. Functionally, treatment with propionate (an agonist of FFAR2) significantly inhibited human A549 or H1299 lung cancer migration, invasion, and colony formation induced by TLR2 or TLR3 through the attenuation of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB. Moreover, FFAR2KO A549 and FFAR2KO H1299 human lung cancer cells showed marked increases in cell migration, invasion, and colony formation in response to TLR2 or TLR3 stimulation, accompanied by elevations in NF-κB activation, cAMP levels, and the production of C-C motif chemokine ligand (CCL)2, interleukin (IL)-6, and matrix metalloproteinase (MMP) 2 cytokines.

Conclusion

Our results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.
Analyzing the role of ACE2, AR, MX1 and TMPRSS2 genetic markers for COVID-19 severity
Authors: Martinez-Diz Silvia , Morales-Álvarez Carmen Maria , Garcia-Iglesias Yarmila , Guerrero-González Juan Miguel , Romero-Cachinero Catalina , González-Cabezuelo Jose María , Fernandez-Rosado Francisco Javier , Arenas-Rodríguez Verónica , Lopez-Cintas Rocío , Alvarez-Cubero Maria Jesús , Martinez-Gonzalez Luis Javier
Published: June 2023

Background

The use of molecular biomarkers for COVID-19 remains unconclusive. The application of a molecular biomarker in combination with clinical ones that could help classifying aggressive patients in first steps of the disease could help clinician and sanitary system a better management of the disease. Here we characterize the role of ACE2, AR, MX1, ERG, ETV5 and TMPRSS2 for trying a better classification of COVID-19 through knowledge of the disease mechanisms.

Methods

A total of 329 blood samples were genotyped in ACE2, MX1 and TMPRSS2. RNA analyses were also performed from 258 available samples using quantitative polymerase chain reaction for genes: ERG, ETV5, AR, MX1, ACE2, and TMPRSS2. Moreover, in silico analysis variant effect predictor, ClinVar, IPA, DAVID, GTEx, STRING and miRDB database was also performed. Clinical and demographic data were recruited from all participants following WHO classification criteria.

Results

We confirm the use of ferritin (p < 0.001), D-dimer (p < 0.010), CRP (p < 0.001) and LDH (p < 0.001) as markers for distinguishing mild and severe cohorts. Expression studies showed that MX1 and AR are significantly higher expressed in mild vs severe patients (p < 0.05). ACE2 and TMPRSS2 are involved in the same molecular process of membrane fusion (p = 4.4 × 10–3), acting as proteases (p = 0.047).

Conclusions

In addition to the key role of TMPSRSS2, we reported for the first time that higher expression levels of AR are related with a decreased risk of severe COVID-19 disease in females. Moreover, functional analysis demonstrates that ACE2, MX1 and TMPRSS2 are relevant markers in this disease.

Graphical abstract
The temporal dynamics of dissociation: protocol for an ecological momentary assessment and laboratory study in a transdiagnostic sample
Authors: Heekerens Johannes B. , Gross James J. , Kreibig Sylvia D. , Wingenfeld Katja , Roepke Stefan
Published: June 2023

Background

Dissociation is a ubiquitous clinical phenomenon. Dissociative disorders (DD) are primarily characterized by dissociation, and dissociative states are also a criterion for borderline personality disorder (BPD) and the dissociative subtype of post-traumatic stress disorder (PTSD). Dissociative reactions (e.g., depersonalization/derealization or gaps in awareness/memory) across diagnostic categories are believed to be affect contingent and theorized to serve affect regulation functions. What is not clear, however, is how self-reported affect and physiological reactivity unfold within dissociative episodes. To address this issue, the present project aims to investigate the hypothesis (1) whether self-reported distress (as indicated by arousal, e.g., feeling tense/agitated, and/or valence, e.g., feeling discontent/unwell) and physiological reactivity increase before dissociative episodes and (2) whether self-reported distress and physiological reactivity decrease during and after dissociative episodes in a transdiagnostic sample of patients with DD, BPD, and/or PTSD.

Methods

We will use a smartphone application to assess affect and dissociation 12 times per day over the course of one week in everyday life. During this time, heart and respiratory rates will be remotely monitored. Afterwards, participants will report affect and dissociative states eight times in the laboratory before, during, and after the Trier Social Stress Test. During the laboratory task, we will continuously record heart rate, electrodermal activity, and respiratory rate, as well as measure blood pressure and take salivary samples to determine cortisol levels. Our hypotheses will be tested using multilevel structural equation models. Power analyses determined a sample size of 85.

Discussion

The project will test key predictions of a transdiagnostic model of dissociation based on the idea that dissociative reactions are affect contingent and serve affect regulation functions. This project will not include non-clinical control participants. In addition, the assessment of dissociation is limited to pathological phenomena.
Successful endovascular thrombectomy with the ClotTriever System for acute subclavian vein thrombosis in venous thoracic outlet syndrome
Authors: Discalzi Andrea , Cignini Valentina , Ciferri Fernanda , Nardelli Floriana , Rossato Denis , Calandri Marco , Fonio Paolo
Published: June 2023

Background

The case describes a successful endovascular thrombectomy using the ClotTriever System for an acute subclavian thrombosis in venous thoracic outlet syndrome. To the best of our knowledge, this is the first case report on use of Inari ClotTriever for acute upper extremity deep venous thrombosis due to venous thoracic outlet syndrome. The rapid technical and clinical success of our intervention may be an interesting cue for interventional radiologist colleagues.

Case presentation

Upper extremity deep vein thrombosis in the setting of venous thoracic outlet syndrome generally occurs in young adults after excessive arm activity and can sometimes be managed with anticoagulation. In this case, a 29-year-old male diagnosed with acute effort-induced thrombosis of the left subclavian vein and persistent symptoms following low-molecular-weight heparin therapy underwent mechanical thrombectomy. Successful thrombectomy was completed with > 90% thrombus burden reduction and no complication. The patient experienced immediate symptom relief and vein patency was confirmed via imaging 3 months post procedure.

Conclusions

Mechanical thrombectomy is a promising treatment technique for thrombosis associated with venous thoracic outlet syndrome.
Delayed iatrogenic diaphragmatic hernia after thoracoscopic resection of diaphragm lipoma
Authors: Oka Soichi , Osaki Toshihiro , Hashimoto Teppei , Kawamura Yuichiro
Published: June 2023

Background

Iatrogenic diaphragmatic hernias have been reported as a rare complication of thoracic and abdominal surgery. We herein report a case of delayed iatrogenic left diaphragmatic hernia after diaphragm pedunculated lipoma resection with minimally invasive surgery.

Case presentation

A 72-year-old Japanese man was found to have an abnormal shadow by medical checkup X-ray and was admitted to our hospital. Chest computed tomography (CT) showed a 5 × 2-cm solid tumor at the left diaphragm. He was diagnosed with a left diaphragm tumor. We performed three-port video-assisted thoracic surgery. This tumor was pedunculated at the left central tendon of the diaphragm. We therefore dissected this tumor using an electric scalpel. Although there was about 5 × 4 mm in diameter slight heat damage to the diaphragm, it was not reinforced because it was very minor injury. He was diagnosed with a left diaphragmatic hernia without any symptoms by routine CT examination which scheduled 1 year after surgery. One day after hospitalization, on the morning of the operation, he suddenly complained of left back pain with acute exacerbation of the left diaphragmatic hernia. We therefore immediately performed emergency surgery and rescued this patient. No adverse events or complications were seen, and he was discharged on postoperative day 11. Three months after this surgery, this patient is doing very well.

Conclusions

Caution should be exercised when using energy devices on the diaphragmatic surface, especially the left side, to avoid causing delayed diaphragmatic hernia. In cases of surgery involving the left-side diaphragm, it seems that careful follow-up after surgery is necessary.
Managing Adverse Effects Associated With Poly (ADP-ribose) Polymerase Inhibitors in Ovarian Cancer: A Synthesis of Clinical Trial and Real-World Data
Authors: Friedlander Michael , Lee Yeh Chen , Tew William P.
Published: June 2023

The use of poly (ADP-ribose) polymerase (PARP) inhibitor therapy is standard care in the management of patients with various malignancies including ovarian, breast, prostate, and pancreatic cancers. PARP inhibitors have been approved in different settings for patients with specific hereditary pathogenic variants, most notably homologous recombination repair pathways such as BRCA1 and BRCA2 genes. The vast experience with PARP inhibitors (olaparib, niraparib, rucaparib) has been in the management of epithelial ovarian cancer. There have not been any head-to-head comparisons of PARP inhibitors in randomized trials, and we can only perform cross-comparison on the basis of the reported literature. The three approved PARP inhibitors share several common adverse effects because of a class effect including nausea, fatigue, and anemia, but there are notable differences likely because of variations in their poly-pharmacology and off-target effects. Finally, patients included in clinical trials are often younger with a good performance status and less comorbidities than the real-world population, and hence, the potential benefits and adverse effects may not be superimposable. In this review, we describe these differences and discuss strategies to mitigate and manage adverse side effects effectively.
Safety of locally administered large surface area microparticle paclitaxel and docetaxel in combination with standard of care cancer therapies.
Authors: Verco Shelagh , Maulhardt Holly , Marin Alyson , Verco Antony
Published: June 2023

e15187

Background: The safety of local delivery of large surface area microparticle paclitaxel (LSAM-PTX) or docetaxel (LSAM-DTX) to solid tumors has been evaluated in Phase 1/2 trials across 156 subjects with 43% (67/156) on various concurrent standard of care (SOC) therapies. Local administration of LSAM-PTX or LSAM-DTX leads to a reduction in systemic drug exposure and drug-related adverse events (AE) and may reduce toxicities encountered in combination systemic treatment regimens. This report summarizes safety findings in subjects co-administered LSAM-PTX or LSAM-DTX and common SOC therapies for treatment of carcinomas. Methods: During the study follow-up periods, AE and serious AE (SAE) were coded (MedDRA 16.1 -23.1) and assessed (NCI CTCAE 3 - 5). Results: In 7 studies (median age 69 years (range 37-96), 61% male, 88% white) (Table), LSAM-PTX administrations occurred as follows: intraperitoneal (n = 31 subjects), intraprostatic (n = 17), and intratumoral (n = 72). A median of 1 cycle (range 1-6) of LSAM-PTX was administered. LSAM-DTX was injected once into bladder tissue after tumor resection followed by a median of 10 cycles (range 7-10) of intravesical instillation in 36 subjects. 59 subjects (median age 65 (range 48-86), 53% male, 88% white) received local LSAM-PTX and concomitant chemotherapy, immunotherapy, or radiation. Rates of subjects who had Grade 3 SAE possibly related to LSAM-PTX were 29%, 24%, 16%, 6.7% and 5.0% in paclitaxel, carboplatin, 5-FU, nab-paclitaxel, and gemcitabine combinations, respectively. Grade 4 SAE possibly related to LSAM-PTX were found in 1 subject each co-administered pembrolizumab (13%), carboplatin (5.9%), and paclitaxel (7.1%). Subjects treated with 5-FU, gemcitabine, and nab-paclitaxel reported no related Grade 4 SAE. No Grade 5 SAE were deemed possibly related to LSAM-PTX. 8 subjects (median age 78 (range 54-89), 100% male, 88% white) received local LSAM-DTX therapy in combination with SOC therapies. No Grade 3-5 AE were reported with LSAM-DTX in combination with gemcitabine, carboplatin, pembrolizumab, avelumab or radiation. Conclusions: Local treatment of solid tumors with LSAM-PTX or LSAM-DTX has the potential to overcome some limitations of SOC therapies by increasing tumor dwell time and reducing systemic toxicities which are often exacerbated in combinatorial treatment regimens. Clinical trial information: NCT00666991 , NCT03636256 , NCT03077659 , NCT04221828 , NCT03029585 , NCT03077685 , NCT04314895 . [Table: see text]
Prevention of chemotherapy-induced neutropenia (CIN) with plinabulin (Plin) vs placebo (Plac) in patients (pts) with non-small cell lung cancer (NSCLC) treated with docetaxel (Doc): A pooled analysis from 3 randomized trials.
Authors: Blayney Douglas W. , Hurley Jasmine , Legaspi Gabrielle , Duprez Stephen , Huang Lan , Mohanlal Ramon W.
Published: June 2023

e21163

Background: CIN can lead to increased patient/healthcare burden, resource utilization, hospitalizations, and poorer quality of life (QoL). G-CSF has a high incidence of bone pain and mild thrombopenia and is given the day after chemo. Plin, a novel non-G-CSF small molecule, protects the bone marrow stem cell, has minimal bone pain, and protects platelet precursors. Plin is given on the same day as chemo and has NSCLC anticancer efficacy (ESMO 2021, Feinstein). The CIN effects of Doc plus Plin vs Doc with Plac were pooled from 3 NSCLC clinical trials. Methods: Data from randomized trials, phase (Ph) 3 trial 103 (NCT02504489), Ph2/3 trial 105 ( NCT03102606 ), and Ph2 trial 101 (NCT00630110) were pooled. Pts were randomized to either Doc (75mg/m2) plus Plin (20mg/m2 or its pharmacokinetic equivalent) (n = 146) or Doc plus Plac (n = 296). Doc was administered on day 1 of each 21-day cycle x 4 cycles, and Plin or Plac was administered ~30 minutes after Doc. Neutrophil counts were taken at predose and day (D) 8 of each cycle in studies 101 & 103, and on predose, D1, 2, 6, 7, 8, 9, 10, 15, and 21 in study 105. Pts given G-CSF in D1-D3 were excluded. Duration of severe neutropenia (DSN) was calculated by methods previously reported (ASH 2022, Blayney). All Grade (Gr) and Gr4 neutropenia (N) rates, Absolute N count (ANC), febrile N (FN) rate, and ANC on D8 (‘nadir’) were obtained. QoL scores were obtained in studies 103 and 105 by EORTC QLQ-C30. Patient-reported adverse events (AEs) were collected. Results: Pt demographics were comparable. Plin was statistically and clinically significantly superior to Plac for All Gr and Gr4 N frequencies, Day 8 ANC (‘nadir’), and DSN (all had p < 0.0001). Febrile Neutropenia (FN) and infection rates were numerically lower (see table). Fewer pts were treated with antibiotics among pts treated with Plin. Platelet count was unaffected with Plin; grade (gr) 3/4 thrombocytopenia was < 1% with either Plin or Plac. The total frequency of treatment-emergent AEs for Plin vs Plac were 71% vs 80%. QoL scores were similar for Plin and Plac. Conclusions: In 3 independent randomized studies (101, 103, and 105), Plin demonstrated a superior benefit for CIN and showed clinical benefit for infection rate versus Plac. Additionally, Plin has the added benefits of pt convenience (same-day dosing and no additional visits or wearable device), a favorable safety and tolerability profile, anticancer efficacy, and QoL maintenance, which represents a distinct advantage over G-CSF. Clinical trial information: NCT02504489 ; NCT03102606 ; NCT00630110 . [Table: see text]
TORCHLIGHT: A randomized, double-blind, phase III trial of toripalimab versus placebo, in combination with nab-paclitaxel(nab-P) for patients with metastatic or recurrent triple-negative breast cancer (TNBC).
Authors: Jiang Zefei , Ouyang Quchang , Sun Tao , Zhang Qingyuan , Teng Yuee , Cui Jiuwei , Wang Haibo , Yin Yongmei , Wang Xiaojia , Zhou Xin , Wang Yongsheng , Sun Gang , Wang Jingfen , Zhang Lili , Yang Jin , Qian Jun , Yi Tienan , Yan Min , Liu Xinlan ,   Shanghai Junshi Biosciences
Published: June 2023

LBA1013

Background: Checkpoint blockade combined with taxanes based chemotherapy had generated mixed results as first line treatment for metastatic TNBC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided significant clinical efficacy with a favorable safety profile in various solid tumors. The purpose of this study is to compare the efficacy and safety of toripalimab versus placebo, in combination with nab-P for metastatic or recurrent TNBC (NCT04085276). Methods: Patients with initially diagnosed metastatic or recurrent inoperable TNBC were randomized 2:1 to receive toripalimab (240mg, D1, q3w) or placebo along with nab-P on days1, 8 in 3-week cycles. Stratifications included PD-L1 expression, paclitaxel therapy history and line of prior therapy at enrollment. Primary endpoint was progression-free survival (PFS) assessed by a blinded independent central review (BICR) per RECIST v1.1, first in the PD-L1-positive population and then in the ITT population. Secondary endpoints included overall survival (OS) and safety. Results: 531 patients were randomized to toripalimab (n = 353) or placebo (n = 178); 200 and 100 patients, respectively had PD-L1 positive TNBC. At interim analysis, with the median follow-up of 14 months, a statistically significant improvement in PFS by BICR was demonstrated for the toripalimab arm in the PD-L1 positive subgroup (mPFS 8.4 vs 5.6 months; HR = 0.653, 95% CI 0.470-0.906, P = 0.0102). The PFS in the ITT population showed a similar trend (mPFS 8.4 vs 6.9 months, HR = 0.773, 95%CI 0.602-0.994). Descriptive analysis of OS showed a trend towards improved OS in the PD-L1 positive (mOS 32.8 vs 19.5 months; HR = 0.615, 95%CI 0.414-0.914) and the ITT population (mOS 33.1 vs 23.5 months; HR = 0.691, 95% CI 0.513-0.932). No new safety signals were identified. Grade≥3 adverse events (AEs) (56.4% vs 54.3%) and fatal AEs (0.6% vs 3.4%) were similar between arms, while AEs leading to discontinuation of toripalimab/placebo (8.5% vs. 3.4%) and immune-related (irAEs) (40.8% vs. 24.0%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1 positive metastatic or recurrent TNBC patients receiving first-line treatment with an acceptable safety profile. Patients will be followed for the final PFS and OS analysis. Clinical trial information: NCT04085276 .
Randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition versus cabozantinib in metastatic soft tissue sarcoma.
Authors: Van Tine Brian Andrew , Eulo Vanessa , Toeniskoetter Jacqui , Ruff Tyler , Luo Jingqin , Kemp Lindsey , Moreno Tellez Cristiam , Weiss Mia C. , Hirbe Angela C. , Meyer Christian Frederick , Elias Anthony D. , Diamond Mark , Hartner Lee P. , Bui Nam , Ganjoo Kristen N. , Maki Robert G. , Wilky Breelyn A.
Published: June 2023

LBA11504

Background: Cabozantinib (C) has been combined successfully with either PD-1 or CTLA-4 inhibition in cancer clinical trials. The combination of nivolumab (N) and ipilimumab (I) previously was evaluated in soft tissue sarcoma (STS) and demonstrated activity as well as an acceptable safety profile. Given these data, we hypothesize that C in combination with both I and N is a therapeutic strategy that will be more effective than C alone in metastatic STS that lack translocations. Additionally, we hypothesized that C priming would enhance the efficacy of combination I and N at the time of crossover. Methods: This is a 2:1 randomized phase 2 clinical trial evaluating the overall response rate (RR) of C 40mg orally daily in combination with I (1mg/kg IV) / N (3mg/kg) for 4 doses Q3W and then maintenance N 480mg Q4W compared to C 60mg oral alone, with crossover. Secondary endpoints include progression free survival (PFS), disease control rate (DCR), RR in crossover, quality of life by FACT-G7, RR by iRECIST and safety. Correlative and biomarker analysis are preplanned. Key patient selection includes ECOG 0-1, 1-2 lines of prior therapy, and sarcomas that lack of translocations. The trial was balanced for leiomyosarcoma (LMS), liposarcoma and UPS. Results: 69 patients were randomized to C+I/N and 36 patients were randomized to C alone. 19 patients crossed over to C+I/N at progression. 54/105 patients had LMS. RR of C+I/N was 11% (5 PR and 2 CR), while the RR of C was 6% (2 PR and 0 CR) (p = NS). C+I/N responding histologies included LMS, angiosarcoma, epithelioid sarcoma, and myxofibrosarcoma. C responding histologies included 2 PRs in LMS. There were also 2 LMS PRs in crossover to C+I/N. The median PFS for C+I/N was 5.4 months and for C was 3.8 months (p = 0.016). The DCR for C+I/N was 80% (41 SD, 5 PR, 2 CR), and 42% for C (11 SD, 2 PR) (p = 0.0004). The most common grade 3-4 adverse events affecting > 10% of patients included hypothyroidism, diarrhea, mucositis, oral dysesthesia, nausea, vomiting, elevated AST and ALT, anorexia, dysgeusia, headache, pruritis, maculopapular rash, and hypertension for C+I/N and hypothyroidism, diarrhea, oral dysesthesia, fatigue, palmar-plantar erythrodysesthesia, and hypertension for C. Conclusions: The combination of C+I/N was superior to C for the treatment of non-translocation STS for DCR and PFS. Most frequent responding histology was LMS. Correlative work is ongoing. Clinical trial information: NCT04551430 .
PROSPECT: A randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048).
Authors: Schrag Deborah , Shi Qian , Weiser Martin R. , Gollub Marc J , Saltz Leonard B. , Musher Benjamin Leon , Goldberg Joel , Al Baghdadi Tareq , Goodman Karyn A. , McWilliams Robert R. , Farma Jeffrey M. , George Thomas J. , Kennecke Hagen Fritz , Venook Alan P. , O'Reilly Eileen Mary , Meyerhardt Jeffrey A. , Dueck Amylou C. , Basch Ethan , Chang George J. , Mamon Harvey J. ,   Alliance for Clinical Trials in Oncology
Published: June 2023

LBA2

Background: Radiation with sensitizing fluoropyrimidine (5FUCRT) is a standard curative intent treatment for LARC. It improves disease-free survival (DFS) by decreasing pelvic recurrence but has short- and long-term toxicity. The PROSPECT trial compares FOLFOX chemotherapy with selective use of 5FUCRT (intervention) to 5FUCRT (control) for neoadjuvant treatment prior to TME for LARC. Methods: Eligible patients (pts) had cT2N+, cT3N-, cT3N+ rectal cancers deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. Pts with distal, T4 tumors, threatened radial margins or > 4 enlarged lymph nodes were ineligible. Pts were randomized 1:1 without blinding. Pts in the control group received 5FUCRT with 5040 cGy over 5.5 weeks with either capecitabine or 5FU. Pts in the intervention group had 6 cycles of mFOLFOX6 followed by restaging. If tumor regression was > 20%, then TME was performed without radiation; if < 20%, 5FUCRT was given before TME. DFS was the 1°outcome, defined as time from randomization to any recurrence or death, analyzed in the per-protocol population. One interim analysis was conducted with α spending = 0.001. Noninferiority (NI) of the intervention could be claimed if the upper limit of the 2-sided 90.2% confidence interval (CI) of the DFS hazard ratio did not exceed 1.29 (NI margin). Secondary endpoints included overall survival (OS), local recurrence free survival, R0 resection, pathologic complete response (CR), and toxicity. Results: From June 2012 to December 2018, 1194, pts were randomized and 1128 initiated protocol-assigned treatment. Median age was 57, 34.5% were women and 61.9% had clinically positive nodes. 53 of 585 pts in the intervention group (9%) received preop 5FUCRT. DFS was analyzed after 227 events and median follow-up of 58 months. Conclusions: FOLFOX chemotherapy with selective use of 5FUCRT is non-inferior to 5FUCRT for neoadjuvant treatment of LARC prior to low anterior resection with TME. Patients and physicians have alternative strategies for management of LARC. Clinical trial information: NCT01515787 . [Table: see text]
PD-1 blockade with sintilimab plus induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) versus IC-CCRT in locoregionally-advanced nasopharyngeal carcinoma (LANPC): A multicenter, phase 3, randomized controlled trial (CONTINUUM).
Authors: Ma Jun , Sun Ying , Liu Xu , Yang Kun-Yu , Zhang Ning , Jin Feng , Zou Guorong , Zhu Xiaodong , Xie Fangyun , He Zhenyu , Chen Nian-Yong , Mao Yan-Ping , Shen Liangfang , Shi Mei , Hong Shu-Bin , Zhao Hongyun , Li Ji-Bin , Tang Ling-Long , Liu Na , Chen Yu-Pei
Published: June 2023

LBA6002

Background: Despite the success of PD-1 blockade plus chemotherapy in recurrent/metastatic NPC, its role in LANPC is unproven. This trial evaluated the efficacy and safety of adding sintilimab (a PD-1 inhibitor) to IC-CCRT in LANPC. Methods: Patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0/T3N1) were enrolled at 9 centers in China, and randomized (1:1; stratified by center and stage with block size four) to the Standard Arm (gemcitabine and cisplatin IC plus cisplatin CCRT), or Sintilimab Arm (sintilimab plus IC-CCRT). Sintilimab 200mg was given intravenously once every 3 weeks for up to 12 cycles (3 induction, 3 concurrent, and 6 adjuvant). The primary endpoint was event-free survival (EFS) (i.e. freedom from local/regional/distant failure or death). It is estimated that approximately 417 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a two-sided type 1 error of 0.05. Quality of life (QoL) was assessed by EORTC-C30. Biomarkers including tertiary lymphoid structure (TLS), PD-L1, and gene expression were also analyzed. Results: Between December 2018, and March 2020, 425 patients were randomized to the Sintilimab Arm (n = 210) and Standard Arm (n = 215). After a median follow-up of 42 months (94% alive patients ≥36 months), the intention-to-treat analysis showed that 3-year EFS was 86.1% in the Sintilimab Arm and 76.0% in the Standard Arm (stratified HR, 0.59; 95% confidence interval [CI], 0.38-0.92; stratified log-rank p = 0.019). Grade 3-4 adverse events (AEs) occurred in 155 (74.2%) and 140 (65.4%) patients, including immune-related AEs in 20 (9.6%) and 2 (0.9%) patients and grade 5 AEs in 2 (0.95%) and 1 (0.5%) patients in the Sintilimab and Standard Arm, respectively (Table). No minimum clinically important differences in QoL were observed. The benefit of the addition of sintilimab was observed in patients with TLS (HR 0.18; 95% CI, 0.04-0.81; p = 0.011) but not in patients without TLS (HR 0.94; 95% CI, 0.50-1.76; p = 0.85). Conclusions: The addition of sintilimab to standard IC-CCRT results in significant improvement of EFS, manageable safety profile, and comparable QoL in high-risk LANPC. TLS appears to be a predictive biomarker for benefit of sintilimab. Clinical trial information: NCT03700476 . [Table: see text]
Distinguishing Renal Cell Carcinoma From Normal Kidney Tissue Using Mass Spectrometry Imaging Combined With Machine Learning
Authors: Shankar Vishnu , Vijayalakshmi Kanchustambham , Nolley Rosalie , Sonn Geoffrey A. , Kao Chia-Sui , Zhao Hongjuan , Wen Ru , Eberlin Livia S. , Tibshirani Robert , Zare Richard N. , Brooks James D.
Published: June 2023

PURPOSE

Accurately distinguishing renal cell carcinoma (RCC) from normal kidney tissue is critical for identifying positive surgical margins (PSMs) during partial and radical nephrectomy, which remains the primary intervention for localized RCC. Techniques that detect PSM with higher accuracy and faster turnaround time than intraoperative frozen section (IFS) analysis can help decrease reoperation rates, relieve patient anxiety and costs, and potentially improve patient outcomes.

MATERIALS AND METHODS

Here, we extended our combined desorption electrospray ionization mass spectrometry imaging (DESI-MSI) and machine learning methodology to identify metabolite and lipid species from tissue surfaces that can distinguish normal tissues from clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC) tissues.

RESULTS

From 24 normal and 40 renal cancer (23 ccRCC, 13 pRCC, and 4 chRCC) tissues, we developed a multinomial lasso classifier that selects 281 total analytes from over 27,000 detected molecular species that distinguishes all histological subtypes of RCC from normal kidney tissues with 84.5% accuracy. On the basis of independent test data reflecting distinct patient populations, the classifier achieves 85.4% and 91.2% accuracy on a Stanford test set (20 normal and 28 RCC) and a Baylor-UT Austin test set (16 normal and 41 RCC), respectively. The majority of the model's selected features show consistent trends across data sets affirming its stable performance, where the suppression of arachidonic acid metabolism is identified as a shared molecular feature of ccRCC and pRCC.

CONCLUSION

Together, these results indicate that signatures derived from DESI-MSI combined with machine learning may be used to rapidly determine surgical margin status with accuracies that meet or exceed those reported for IFS.
Age and Gender Adjusted FT3 Levels as Novel Predictors of Survival
Authors: Strich David , Israel Ariel , Edri Shalom , Gillis David
Published: June 2023

Context

Lower levels of free T3 (FT3) occur during acute illness, as part of “euthyroid sick syndrome.” A chronic form of this syndrome also exists.

Objective

To determine whether thyroid hormone levels predict long-term survival.

Design and Setting

This was a “big-data” study of thyroid function tests from samples taken between 2008 and 2014. Data were crossed with electronic health records for morbidity and mortality. Test results were converted to age- and gender-adjusted percentiles (AGAPs). The hazard ratio for death was crossed with ranges of initial AGAPs and change in AGAPs for 2 subgroups: “not healthy” (subjects with at least 1 of 5 chronic conditions registered in their electronic health chart) and “healthy” (all others).

Participants

2 453 091 sets of thyroid function tests from 365 965 distinct patients were evaluated. 258 695 sets remained after excluding patients registered as taking thyroid preparations or anti-thyroid drugs.

Main Outcome Measure

Hazard ratio for death, planned before data collection.

Results

The cohort included 151 868 not healthy and 106 827 healthy people. After a median of 6.8 years, 5865/151 868 (10.4%) of the not healthy had died and 2504/106 827 (2.3%) of healthy participants. Low initial FT3 AGAPs were predictive of poor survival. The hazard ratio for survival compared between the lowest 5 and highest 50 percentiles of initial FT3 AGAPs for not healthy participants was 5.71 [confidence interval (CI) 5.23-6.26, P < .001] and for healthy was 3.92 (CI 3.06-5.02, P < .001).

Conclusion

Low FT3 AGAPs predicted poor survival, most strongly among not healthy people.
Ελληνο-αρμενικές σχέσεις και η ελληνική στάση και πολιτική απέναντι στους Αρμένιους και το αρμενικό ζήτημα (1945-1975)
Authors: Ντιλσιζιάν Λεβόν-Λεωνίδας
Published: June 2023

Η παρούσα μελέτη επιχειρεί να ρίξει φως στο ερευνητικό κενό που παρατηρείται σε σχέση με την παρουσία των Αρμενίων στον ελληνικό χώρο και τις σχέσεις τους με το ελληνικό κράτος κατά την μεταπολεμική περίοδο (1945-1975). Παρότι η παρουσία άλλων μειονοτικών ομάδων έχει διερευνηθεί τουλάχιστον σε ένα στοιχειώδες βαθμό και παρά το γεγονός ότι οι Αρμένιοι στον ελληνικό χώρο έχουν διαχρονική παρουσία ακόμη και νωρίτερα από τον 17ο αιώνα, η μέχρι σήμερα ερευνητική προσπάθεια έχει καλυφθεί μόνο αποσπασματικά και για ορισμένες τοπικές κοινότητες, παρουσιάζοντας σημαντικά κενά, ιδίως κατά τη νεότερη περίοδο. Συγκεκριμένα, διερευνάται η ελληνική στάση και πολιτική απέναντι στους Αρμένιους της Ελλάδας για μια περίοδο 30 ετών, από το 1945 και μέχρι το 1975, με έμφαση στα κύρια ζητήματα που τίθενται από την παρουσία των Αρμενίων στην Ελλάδα, ερμηνεύοντας παράλληλα την στάση και τους λόγους της ελληνικής επίσημης και ανεπίσημης πλευράς απέναντι στην αρμενική κοινότητα της χώρας. Με σημείο έναρξης το έτος 1945, μεταξύ των κύριων ζητημάτων και γεγονότων που θίγονται είναι το μεγάλο κύμα «επαναπατρισμού» από την Ελλάδα προς τη Σοβιετική Αρμενία κατά τη διάρκεια του Ελληνικού Εμφυλίου και τα αιτήματα της αρμενικής κοινότητας για τα θέματα της εκπαίδευσης, της ιθαγένειας, της στέγασης και της νομικής προσωπικότητας της ίδιας της κοινότητας, δηλαδή ζητήματα που διατρέχουν την καθημερινότητα των Αρμενίων και της ίδια της κοινότητας σε όλη τη διάρκεια του Ψυχρού Πολέμου, και η διασύνδεσή τους με το ελληνικό κράτος, με διάκριση σε επιμέρους χρονικές περιόδους που επιτρέπουν την κατανόηση της ελληνικής στάσης απέναντι στους Αρμένιους της Ελλάδας, ενώ ταυτόχρονα επιχειρείται να απαντηθούν οι λόγοι που οδηγούν σε μια θετική ή αρνητική προσέγγιση κάθε φορά, υπό το πρίσμα της ιστορικής εποχής που διερευνάται.
Nontruthful Position Auctions Are More Robust to Misspecification
Authors: Dütting Paul , Fischer Felix , Parkes David C.
Published: June 2023

We consider the classical model of sponsored search due to Edelman et al. and Varian and examine how robust standard position auctions are to a misspecification of the position-dependent quality factors used by this model. We show that under both complete and incomplete information a nontruthful position auction admits an efficient equilibrium for a strictly broader range of parameter values than the Vickrey-Clarke-Groves (VCG) mechanism, which would be truthful if the parameters were specified correctly. Our result for complete information concerns the generalized second-price (GSP) mechanism and is driven by a detailed understanding of the Nash equilibrium polytopes of the VCG mechanism and the GSP mechanism. Our result for incomplete information concerns the generalized first-price (GFP) mechanism and uses a surprising connection between the unique candidate equilibrium bidding functions of the VCG mechanism and the GFP mechanism.

Funding: F. Fischer was supported by the Engineering and Physical Sciences Research Council [Grant EP/T015187/1] and Einstein Stiftung Berlin.
What next for the early years charity managed sector?
Authors: Gridley Sally
Published: June 2023

Sally Gridley, owner of Dinky Ones Early Years Consultancy, takes a look at the challenges facing the charity managed early years sector and discusses possible solutions to ensure long term stability.
Ocorrência, Distribuição e análise da alimentação de peixes da família Carangidae (Actinopterygii, Carangiformes) na Baía de Todos os Santos, BA
Authors: Rianne Paim Evangelista de Andrade  , Alexandre Clistenes de Alcantara Santos
Published: June 2023

A Baía de Todos os Santos (BTS) possui uma alta biodiversidade e apesar disso, estudos sobre a estrutura da ictiofauna presente nesse ecossistema costeiro-marinho ainda são escassos e\ou pontuais, sendo que relativamente poucas questões com relação à ictiofauna da BTS foram abordadas, tais como: alimentação (Oliveira-Silva & Lopes, 2002; Santos et al, 2007; Santos, 2009); novos registros de espécies (Santos et al, 2009 Lopes & Oliveira-Silva, 2002; Lopes et al. 2001) e avaliação da composição e/ou estrutura de comunidade (Santos et al. 1999; Santos et al, 2020; Lima, 2018). Desta forma, informações pormenorizadas sobre uma família de peixes de alta importância comercial, como Carangidae, ajudará na obtenção de fundamentos, que permitirão conhecer e preservar a ictiofauna e os ambientes costeiros da Baía de Todos os Santos.
Extractivism and capitalism in the era of neoliberal globalisation: development and resistance dynamics in Latin America
Authors: Veltmeyer Henry
Published: June 2023

This article explores the development and resistance dynamics of capital in the neoliberal era of capitalist development. The context for this exploration is Latin America, the region that has been most severely impacted by the globalising dynamics of the world capitalist system, which is in the throes of a multidimensional crisis that has assumed global proportions. The region has also seen the most powerful forces of resistance to this development, a resistance led by the Indigenous and farming communities on the extractive frontier. It is argued that each advance of capital in the development process, that is, each phase in the capitalist development of the forces of production – from the colonial era of mercantilism and extractive imperialism to the era of neoliberal globalisation – has generated corresponding forces of resistance, leading to a succession of development–resistance cycles in the evolution of capitalism as a world system.
Girl Power Through Purchasing?: The Urban, Young, Educated, Working, Indian Woman and Aspirational Images in Personal Care and Beauty Aid Advertisements
Authors: Schwartz Suzanne L.
Published: June 2023

This article explores the changing aspirations, economic positions, and social concepts of urban, young, educated, working women in India. This exploration focuses on how these Indian women are imagined and re-imagined in advertisements for personal care and beauty aid products, specifically those for Lakmé cosmetics. The article is based on the advertisements for Lakmé cosmetics, an Indian cosmetics brand, from the fall 2008 through the summer 2009 and six months of fieldwork in 2009 at the Mumbai-based advertising agency that created these advertisements. The advertisements are discussed within the broader context of the Indian economy, consumerism, and representation of women in the media. Furthermore, by focusing on the beliefs and experience of the female advertisers who helped to create Lakmé's advertisements, the article seeks to understand how working Indian women perceive themselves vis-à-vis these advertising images.
Do Payroll Tax Breaks Stimulate Formality?: Evidence from Colombia’s Reform
Authors: Kugler Adriana D. , Kugler Maurice D. , Herrera-Prada Luis O.
Published: June 2023

Alternative work arrangements have grown rapidly around the world. In Latin America, these alternative work arrangements have long been part of the labor market and have continued to grow. The informal sector grew rapidly in Latin America over the past few decades comprising up to half of the working population in many countries. Some attribute the growth in alternative work arrangements and informality to regulations and taxes, while others argue that it is precisely the lack of enforcement of regulations that allows unprotected employment arrangements to flourish. We examine whether reducing taxes associated with employment stimulates formal sector employment. We exploit the fact that the tax reform introduced in Colombia in 2012 affected only certain types of workers and not others. In particular, workers earning less than ten times the minimum wage and self-employed workers with more than two employees experienced a reduction of payroll taxes of 13.5 percent between 2013 and 2014. We use the Colombian household surveys, social security records and the monthly manufacturing sample to conduct difference-in-differences analyses of the reform. We find evidence of increased formal employment for the affected groups after the reform using all three data sets. We find that the probability of formal employment and the likelihood of transitioning into registered employment increased for the affected groups after the reform. We also find that the level and share of permanent employment relative to temporary employment grew after the reform for those earnings less than ten times the minimum wage. The results are greatest for those in smaller firms and for those earnings close to the minimum wage.
Enigmatic Epistolarity: Twombly's Letter of Resignation
Authors: Schwenger Peter
Published: June 2023

Looking at first merely like 38 scribbled pages, Cy Twombly's Letter of Resignation shows how writing's essence, as Roland Barthes argues, is most evident when it is illegible. The series illuminates letter-writing as a process; writing's relation to drawing; and the way the hand's traces reveal the emotions that impelled it.
Learning to detect 3D planes from a single plenoptic image
Authors: Gao Sihao , Li Jun , Wang Ping , Xu Xiaojun
Published: June 2023

In this paper, we propose a deep neural network to detect 3D planar surfaces from single plenoptic images captured by a Lytro Illum camera. Different from learning methods based on a single RGB image, we train a network to exploit the light distribution information both in spatial and angular dimensions from multi-sub-aperture images. The features from each sub-aperture image are extracted by using parameter-sharing convolutional layers and then fused to jointly infer the parameters of planes, depths, and segmentation masks. The experiments demonstrate that our approach outperforms the existing state-of-the-art methods with significant margins in the plane detection metrics.
Optimizing LERP systems: opto-thermal steady-state simulation analysis and experimental validation
Authors: Chatzizyrli Elisavet , Afentaki Angeliki , Hinkelmann Moritz , Lachmayer Roland , Neumann Jörg , Kracht Dietmar
Published: June 2023

Laser-excited remote phosphor (LERP) systems are the next step in solid-state lighting technology. However, the thermal stability of phosphors has long been a major concern in the reliable operation of these systems. As a result, a simulation strategy is presented here that couples the optical and thermal effects, while the phosphor properties are modeled to temperature. A simulation framework is developed in which the optical and thermal models are defined in Python using appropriate interfaces to commercial software: the ray tracing software Zemax OpticStudio for the optical analysis and the finite element method (FEM) software ANSYS Mechanical for the thermal analysis. Specifically, the steady-state opto-thermal analysis model is introduced and experimentally validated in this study based on Ce:YAG single-crystals with polished and ground surfaces. The reported experimental and simulated peak temperatures are in good agreement for both the polished/ground phosphors in the transmissive and reflective setups. A simulation study is included to demonstrate the simulation’s capabilities for optimizing LERP systems.
Research on accurate non-contact temperature measurement method for telescope mirror
Authors: Huang Shanjie , Wang Lingxue , Hu Xu , Yuan Shouzhang , Xu Fangyu , Zhao Jinsong , Cai Yi
Published: June 2023

Non-contact temperature measurement for a solar telescope mirror is critical for improving the mirror seeing and thermal deformation of solar telescopes, a long-standing challenge in astronomy. This challenge arises from the telescope mirror’s inherent weak thermal radiation, often overwhelmed by reflected background radiations due to its high reflectivity. In this work, an infrared mirror thermometer (IMT) is equipped with a thermally-modulated reflector, and a measurement method based on an equation for extracting mirror radiation (EEMR) has been developed for probing the accurate radiation and temperature of the telescope mirror. Using this approach, we can extract the mirror radiation from the instrumental background radiation via the EEMR. This reflector has been designed to amplify the mirror radiation signal incident on the infrared sensor of IMT, while inhibiting the radiation noise from the ambient environment. In addition, we also propose a set of evaluation methods for IMT performance based on EEMR. The results reveal that the temperature measurement accuracy of IMT to the solar telescope mirror using this measurement method can be achieved better than ±0.15°C.
Defect detection and response non-uniformity correction of a monocentric camera based on fiber optic relay imaging
Authors: Xie Dandan , Huang Yawei , Yan Changxiang
Published: June 2023

The monocentric camera based on fiber relay imaging offers benefits of light weight, compact size envelope, vast field of view, and high resolution, which can fully fulfill the index requirements of space-based surveillance systems. However, the fiber optic plate's (FOP) defects will result in the loss of imaging data, and the FOP's discrete structural features will exacerbate the imaging's non-uniformity. A global defect detection approach based on manual threshold segmentation of saturated frames is suggested to detect FOP defect features. The suggested method's efficacy and accuracy are confirmed when compared to the classical Otsu algorithm. Additionally, through tests, the relative imaging response coefficients of each pixel are identified, the response non-uniformity of the pixels is corrected, and the whole image non-uniformity drops from 10.01% to 0.78%. The study in this paper expedites the use of fiber relay imaging-based monocentric cameras in the field of space-based surveillance, and the technique described in this paper is also appropriate for large-array optical fiber coupled relay image transmission systems.
Multi-color complex spatial light modulation with a single digital micromirror device
Authors: Yan Hengzhe , Sun Yuncong , Lin Yiqiao , Chu Feixiang , Wan Wenjie
Published: June 2023

Spatial light modulators enabling complex light field manipulation has opened up many opportunities in biomedical imaging, holographic display, and adaptive optics. However, traditional spatial light modulators do not allow multi-color operations simultaneously due to their physical constraints, while multi-color modulations are highly desirable in many applications. To overcome this limitation, we demonstrate a multi-color spatial complex light field modulation with a single binary hologram on digital micromirror devices (DMD). This method combines several neighboring micro-mirror pixels into a giant single superpixel, in which the light field’s amplitude and phase can be individually determined by internal pixel combinations, and the dynamic range of phase modulation can exceed 2π for the single wavelength. As a result, this extra phase modulation range offers an additional degree of freedom for independent multi-wavelength light modulation. Based on this scheme, multi-color light modulations have been demonstrated in a 2D plane as well as in multiple 3D holographic planes. Moreover, a dual-colored Airy beam has been realized using the same technique. These results bring complex light modulation into a multi-color regime, paving the way for practical applications in information display, imaging, and optical trapping.