Publications by authors named "Lin Shen"

774 Publications

Perceived daily sleep need and sleep debt in adolescents: associations with daily affect over school and vacation periods.

Sleep 2021 Jul 29. Epub 2021 Jul 29.

Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Australia.

Study Objectives: To describe trajectories of perceived daily sleep need and sleep debt, and examine if cumulative perceived sleep debt predicts next-day affect.

Methods: Daily sleep and affect were measured over 2 school weeks and 2 vacation weeks (N=205, 54.1% females, M±SDage = 16.9±0.87 years). Each day, participants wore actigraphs and self-reported the amount of sleep needed to function well the next day (i.e., perceived sleep need), sleep duration, and high- and low-arousal positive and negative affect (PA, NA). Cumulative perceived sleep debt was calculated as the weighted average of the difference between perceived sleep need and sleep duration over the past 3 days. Cross-lagged, multilevel models were used to test cumulative sleep debt as a predictor of next-day affect. Lagged affect, day of the week, study day, and sociodemographics were controlled.

Results: Perceived sleep need was lower early in the school week, before increasing in the second half of the week. Adolescents accumulated perceived sleep debt across school days and reduced it during weekends. On weekends and vacations, adolescents self-reported meeting their sleep need, sleeping the amount, or more than the amount of sleep they perceived as needing. Higher cumulative actigraphy sleep debt predicted higher next-day high arousal NA; higher cumulative diary sleep debt predicted higher NA (regardless of arousal), and lower low arousal PA the following day.

Conclusion: Adolescents experienced sustained, cumulative perceived sleep debt across school days. Weekends and vacations appeared to be opportunities for reducing sleep debt. Trajectories of sleep debt during vacation suggested recovery from school-related sleep restriction. Cumulative sleep debt was related to affect on a daily basis, highlighting the value of this measure for future research and interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsab190DOI Listing
July 2021

Interventions to Support Mental Health among Those with Health Conditions That Present Risk for Severe Infection from Coronavirus Disease 2019 (COVID-19): A Scoping Review of English and Chinese-Language Literature.

Int J Environ Res Public Health 2021 07 7;18(14). Epub 2021 Jul 7.

Arthur Labatt School of Nursing, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada.

This study aimed to address knowledge gaps related to the prevention and management of mental health responses among those with a condition that presents risk of severe COVID-19 infection. A scoping review that mapped English and Chinese-language studies (2019-2020) located in MEDLINE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, Sociological Abstracts, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Airiti Library was undertaken. Search terms related to COVID-19, mental health, and physical health were used and articles that included all three of these factors were extracted ( = 77). With the exception of one hospital-based pilot study, there were no intervention studies targeting mental health in those at risk of severe COVID-19 infection. Promising practices such as integrated care models that appropriately screen for mental health issues, address health determinants, and include use of digital resources were highlighted. Patient navigator programs, group online medical visits, peer support, and social prescribing may also support those with complex needs. Future policies need to address digital health access inequities and the implementation of multi-integrated health and social care. Furthermore, research is needed to comprehensively assess multi-integrated interventions that are resilient to public health crises.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18147265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303838PMC
July 2021

Genetic differences between lung metastases and liver metastases from left-sided microsatellite stable colorectal cancer: next generation sequencing and clinical implications.

Ann Transl Med 2021 Jun;9(12):967

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Data regarding the clinical characteristics and outcomes of lung metastases (LuM) from colorectal cancer (CRC) are different from those of liver metastases (LiM) from CRC. However, little is known about the genetic features of LuM. This study aimed to identify the different genetic characteristics of LuM and LiM from left-sided microsatellite stable CRC.

Methods: Tissue samples of the primary tumors and paired metastases from 18 CRC patients with isolated LuM (LuM cohort), 18 patients with isolated LiM (LiM cohort), and 10 locally advanced CRC patients without metastases (control cohort) were selected for next-generation sequencing. Patients in the LiM cohort had matched clinicopathological characteristics with the LuM cohort. The single-nucleotide variations (SNVs), copy number variations (CNVs), pathway alterations, and tumor mutation burdens (TMBs) were also calculated and analyzed.

Results: The CNV results showed that , and amplifications were more common in the metastatic cohorts than in the control cohort, while and amplifications were common in the controls. The LuM cohort had significantly higher proportions of , and amplification. The LuM, LiM, and control cohorts were successfully separated using pathway alteration analysis. The LuM cohort had more frequent alterations in the RTK/RAS pathway, HIPPO pathway, , and than the LiM group. The LuM cohort also had relatively higher TMBs than the LiM cohort.

Conclusions: CNVs in primary tumors could identify patients with LuM. Targeting the HIPPO pathway or and immune checkpoint inhibitors (ICIs) combined with other agents might be novel therapies for LuM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-21-2221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267278PMC
June 2021

Copper-Catalyzed Chloro-Arylsulfonylation of Styrene Derivatives via the Insertion of Sulfur Dioxide.

Org Lett 2021 Jul 14. Epub 2021 Jul 14.

Department of Dermatology, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital and West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China.

A copper-catalyzed four-component chloro-arylsulfonylation of styrene derivatives with aryldiazonium tetrafluoroborates, lithium chloride, and generated sulfur dioxide (from SOgen) is presented. This sulfonylation features good functional group compatibility, mild reaction conditions, excellent regioselectivity, and good yields. The robustness and potential of this method have also been successfully demonstrated by a gram-scale reaction. Based on experimental study, a radical-involved mechanism is proposed for the transformation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.1c02001DOI Listing
July 2021

Proteomics provides individualized options of precision medicine for patients with gastric cancer.

Sci China Life Sci 2021 Jul 9. Epub 2021 Jul 9.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.

While precision medicine driven by genome sequencing has revolutionized cancer care, such as lung cancer, its impact on gastric cancer (GC) has been minimal. GC patients are routinely treated with chemotherapy, but only a fraction of them receive the clinical benefit. There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy. Here, we carried out retrospective analyses of 1,020 formalin-fixed, paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC. We identified two proteomic subtypes: the chemo-sensitive group (CSG) and the chemo-insensitive group (CIG) in the discovery set. The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (64.2% vs. 49.6%; Cox P-value=0.002), whereas no such improvement was observed in CIG (50.0% vs. 58.6%; Cox P-value=0.495). We validated these results in an independent validation set. Further, differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC. A prospective study is warranted to test these findings for future GC patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11427-021-1966-4DOI Listing
July 2021

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

Lancet Oncol 2021 Jul 9. Epub 2021 Jul 9.

Department of General Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China.

Background: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.

Methods: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral capecitabine 1000 mg/m twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.

Findings: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.

Interpretation: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.

Funding: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(21)00297-7DOI Listing
July 2021

Evaluation of Tucatinib in HER2-Positive Breast Cancer Patients With Brain Metastases: A United States-Based Cost-Effectiveness Analysis.

Clin Breast Cancer 2021 Jun 12. Epub 2021 Jun 12.

Department of Pharmacy, First Affiliated Hospital of Fujian Medical University, Taijiang, Fuzhou, China. Electronic address:

Purpose: To evaluate the cost-effectiveness of tucatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastases (BMs) and the subgroup of active BMs from the United States (US) payer perspective.

Materials And Methods: A 3-state Markov model was developed to compare the cost-effectiveness of 2 regimens in HER2-positive BC patients with BMs: (1) tucatinib, trastuzumab, and capecitabine (TTC); (2) placebo, trastuzumab, and capecitabine (PTC). And subgroup analysis of active BMs was also performed. Lifetime costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB) were estimated. The willingness-to-pay (WTP) threshold was $200,000/QALY. The robustness of the model was tested by sensitivity analyses. Additional scenario analysis was also performed.

Results: Compared with PTC, the ICER yielded by TTC was $418,007.01/QALY and the INHB was -1.08 QALYs in patients with BMs. In the subgroup of active BMs, the ICER and the INHB were $324,465.03/QALY and -0.71 QALY, respectively. The results were most sensitive to the cost of tucatinib. Probabilistic sensitivity analyses suggested that the cost-effective probability of TTC was low at the current WTP threshold in the patients with BMs and the subgroup of active BMs.

Conclusion: Tucatinib is unlikely to be cost-effective in HER2-positive BC patients with BMs from the US payer perspective but shows better economics in patients with active BMs. Selecting a favorable population, reducing the price of tucatinib or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of tucatinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clbc.2021.06.001DOI Listing
June 2021

Hemifacial Spasm: Comparison of Results between Patients Older and Younger than 70 Years Operated on with Microvascular Decompression.

J Neurol Surg A Cent Eur Neurosurg 2021 Jul 8. Epub 2021 Jul 8.

Neurosurgery Department, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective:  The aim of the present study was to evaluate the efficacy and safety of microvascular decompression (MVD) for primary hemifacial spasm (HFS) in patients aged ≥70 years and to compare the outcome with a control cohort of younger patients(<70 years).

Methods:  In this retrospective study, subjects were divided into two groups: an elderly group (patients who were ≥70 years) and a younger group. We compared demographic and clinical data, surgical outcome, MVD-related complications, and duration of operation and hospitalization after MVD between the two groups.

Results:  At a mean follow-up of 32 ± 4.2 months, 188 elderly patients (90.4%) reported an effective outcome without need for any medication versus 379 (91.1%) of the younger cohort. There was no mortality in both cohorts. The prevalence of delayed facial palsy was 4.8% in the elderly group and 4.1% in the younger group. One (0.5%) patient in the elderly group and 3 (0.7%) patients in the younger group suffered cerebrospinal fluid (CSF) leakage. There was no significant difference between the two groups in terms of MVD-related complications, such as delayed facial palsy, hearing impairment, CSF leakage, and hematoma.

Conclusions:  MVD is an effective treatment option in elderly patients with HFS as well as in younger patients. Age itself seems to be no relevant contraindication or, alternatively, risk factor regarding MVD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1721018DOI Listing
July 2021

Improving perinatal sleep via a scalable cognitive behavioural intervention: findings from a randomised controlled trial from pregnancy to 2 years postpartum.

Psychol Med 2021 Jul 7:1-11. Epub 2021 Jul 7.

Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.

Background: Sleep disturbance is common in gestational parents during pregnancy and postpartum periods. This study evaluated the feasibility and efficacy of a scalable cognitive behavioural therapy (CBT) sleep intervention tailored for these periods.

Methods: This is a two-arm, parallel-group, single-blind, superiority randomised controlled trial. Nulliparous females without severe medical/psychiatric conditions were randomised 1:1 to CBT or attention- and time-matched control. All participants received a 1 h telephone session and automated multimedia emails from the third trimester until 6 months postpartum. Outcomes were assessed with validated instruments at gestation weeks 30 (baseline) and 35 (pregnancy endpoint), and postpartum months 1.5, 3, 6 (postpartum endpoint), 12 and 24.

Results: In total, 163 eligible participants (age M ± s.d. = 33.35 ± 3.42) were randomised. The CBT intervention was well accepted, with no reported adverse effect. Intention-to-treat analyses showed that compared to control, receiving CBT was associated with lower insomnia severity and sleep disturbance (two primary outcomes), and lower sleep-related impairment at the pregnancy endpoint (p values ⩽ 0.001), as well as at 24 months postpartum (p ranges 0.012-0.052). Group differences across the first postpartum year were non-significant. Participants with elevated insomnia symptoms at baseline benefitted substantially more from CBT (v. control), including having significantly lower insomnia symptoms throughout the first postpartum year. Group differences in symptoms of depression or anxiety were non-significant.

Conclusions: A scalable CBT sleep intervention is efficacious in buffering against sleep disturbance during pregnancy and benefitted sleep at 2-year postpartum, especially for individuals with insomnia symptoms during pregnancy. The intervention holds promise for implementation into routine perinatal care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0033291721001860DOI Listing
July 2021

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021.

Cancer Commun (Lond) 2021 Jul 1. Epub 2021 Jul 1.

Department of Gastrointestinal Medical Oncology, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, 150081, P. R. China.

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cac2.12193DOI Listing
July 2021

Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors.

J Hematol Oncol 2021 Jun 21;14(1):95. Epub 2021 Jun 21.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.

Background: Monoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously.

Methods: This open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival.

Results: One hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0-52.8), and the disease control rate was 66.0% (95% CI 56.0-75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5-97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7-82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1-2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events.

Conclusions: This is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer. Trial registration ClinicalTrials.gov, NCT03667170. Registered 10 September 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03667170 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-021-01095-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218452PMC
June 2021

Response to the rechallenge of combination immunotherapy in a patient with late-stage gastric cancer: case report.

Ann Palliat Med 2021 Jun 11. Epub 2021 Jun 11.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China.

Until present, late-stage gastric cancer (GC) remains a refractory disease featured with poor prognosis. However, the upcoming era of immunotherapy turns situations around. Programmed death-1 receptor (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade, an option of immune checkpoints inhibiting, has gained approval for the third-line treatment of patients with locally advanced and/or metastatic GC. Despite its efficacy in a few tumor subtypes, most patients are insensitive to anti-PD-1 monotherapy. Therefore, growing interests arise in combination immunotherapy. To explore the maximal potentials of ICI, oncologists also focus on ICI rechallenge. Here we present a patient with unresected stage IV, Epstein-Barr virus (EBV) unrelated, microsatellite stable and HER2 heterogeneously expressed gastric adenocarcinoma who experienced the failures of previous immunotherapy. He was then rechallenged with identical ICI regime combined with tyrosine kinase inhibiting and anti-HER2 therapy. The patient responded and tolerated well to this regimen and survived with fair living quality after 28 months of treatment. This case suggests that patients who fail frontline immunotherapy still possibly benefit from rechallenge of the same anti-PD-1 regimen. Besides, combination of ICI and other target agents might intrigue a synergistic effect, resulting in enhanced anti-tumor effect, which provides a meaningful therapeutic strategy. Relevant studies are underway of investigation and might be a hotspot for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/apm-21-83DOI Listing
June 2021

Profiling heterogenous sizes of circulating tumor microemboli to track therapeutic resistance and prognosis in advanced gastric cancer.

Hum Cell 2021 Jun 21. Epub 2021 Jun 21.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Fucheng Road 52, Haidian District, Beijing, 100142, China.

Circulating tumor microemboli (CTM) aggregated by ≥ 2 circulating tumor cells (CTCs) are more migratory than single CTCs. Aside from the plasticity in their molecular characteristics, which have been considered tumor migration, CTM also possesses high size heterogeneity. This study, therefore, systematically investigated the heterogeneous sizes of CTM and their involvement in therapeutic resistance in 114 patients with advanced gastric cancer (GC) using a pre-established surface molecule-independent subtraction enrichment (SE)-iFISH strategy. CTM, which was pre-therapeutically detected in 33.3% of GC patients, can further form in another 34.78% of patients following chemo-/targeted therapies. The presence of CTM is relevant to liver metastasis as well as higher CTC levels (≥ 5/6 mL). Further size-based profiling of GC-CTM revealed that CTM with 2 CTCs (CTM) was the dominant subtype, accounting for 50.0% of all detected GC-CTMs. However, CTM with 3-4 CTCs (CTM) specifically associates with chemo-/targeted therapeutic resistance and inferior prognosis. Patients with ≥ 1 CTM/6 mL have shorter median progression-free survival and median overall survival. Unlike CTM and CTM, which are detectable in pre-therapy and post-therapy, larger aggregated CTM (CTM with ≥ 5 CTCs) was only intra-therapeutically detected in four HER2 GC patients, of which three experienced liver metastases. Obtained results suggested that the cluster size of GC-CTM should be dynamically profiled beyond pre-therapeutic whole CTM enumeration in terms of chemo-/targeted resistance or metastasis monitoring. GC-CTM could be a potential indicator of therapeutic resistance, while the dynamic presence of GC-CTM implies liver metastasis in HER2 GC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13577-021-00568-2DOI Listing
June 2021

Axotomy Induces Drp1-Dependent Fragmentation of Axonal Mitochondria.

Front Mol Neurosci 2021 3;14:668670. Epub 2021 Jun 3.

Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.

It is well established that CNS axons fail to regenerate, undergo retrograde dieback, and form dystrophic growth cones due to both intrinsic and extrinsic factors. We sought to investigate the role of axonal mitochondria in the axonal response to injury. A viral vector (AAV) containing a mitochondrially targeted fluorescent protein (mitoDsRed) as well as fluorescently tagged LC3 (GFP-LC3), an autophagosomal marker, was injected into the primary motor cortex, to label the corticospinal tract (CST), of adult rats. The axons of the CST were then injured by dorsal column lesion at C4-C5. We found that mitochondria in injured CST axons near the injury site are fragmented and fragmentation of mitochondria persists for 2 weeks before returning to pre-injury lengths. Fragmented mitochondria have consistently been shown to be dysfunctional and detrimental to cellular health. Inhibition of Drp1, the GTPase responsible for mitochondrial fission, using a specific pharmacological inhibitor (mDivi-1) blocked fragmentation. Additionally, it was determined that there is increased mitophagy in CST axons following Spinal cord injury (SCI) based on increased colocalization of mitochondria and LC3. models revealed that mitochondrial divalent ion uptake is necessary for injury-induced mitochondrial fission, as inhibiting the mitochondrial calcium uniporter (MCU) using RU360 prevented injury-induced fission. This phenomenon was also observed . These studies indicate that following the injury, both and , axonal mitochondria undergo increased fission, which may contribute to the lack of regeneration seen in CNS neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnmol.2021.668670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209475PMC
June 2021

The neuroprotective role of morroniside against spinal cord injury in female rats.

Neurochem Int 2021 Sep 17;148:105105. Epub 2021 Jun 17.

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College, 287 Chang Huai Road, Bengbu, 233004, PR China; Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, 233004, PR China. Electronic address:

Spinal cord injury (SCI) is a disabling condition that often leads to permanent neurological deficits without an effective treatment. Reactive oxygen species (ROS) produced during oxidative stress play a vital role in the pathogenesis following SCI. The antioxidant morroniside is the main active component of the Chinese medicine Cornus officinalis. In recent years, it has been reported that morroniside has therapeutic effects on damage to multiple organs mediated by oxidative damage, but the effect of morroniside on SCI has not been reported. The purpose of this study was therefore to assess the therapeutic effect of morroniside on SCI, and to identify its underlying mechanism by direct intragastric administration immediately after SCI. Our study showed that morroniside treatment improved the functional recovery of rats following SCI. This behavioral improvement was associated with the higher survival in neurons and oligodendrocytes following SCI, which increased the capacity of injured spinal cord (SC) to form myelin and repair tissue, eventually contributing to improved neurological outcome. Furthermore, our study found that oxygen free radicals increased and antioxidant enzyme activity decreased in the injured SC. Interestingly, morroniside treatment decreased oxygen free radical levels and increased antioxidant enzyme activities. Together, our results suggested that morroniside may be an effective treatment for improving outcomes following SCI, and that its antioxidant activity may be one of the mechanisms by which morroniside exerts neuroprotective effects on SCI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2021.105105DOI Listing
September 2021

Evaluation of mixed quantum-classical molecular dynamics on -azobenzene photoisomerization.

Phys Chem Chem Phys 2021 Jun;23(25):13951-13964

Key Laboratory of Theoretical and Computational Photochemistry of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.

The quantitative prediction of nonadiabatic transitions between different electronic states is important to understand ultrafast processes in photochemistry. A variety of mixed quantum-classical molecular dynamics methods such as surface hopping and Ehrenfest mean-field have been developed. However, how to choose an appropriate one from a wide diversity of dynamics algorithms to study a realistic photochemical process is still unclear. In this work, we implemented 30 combinations of different mixed quantum-classical dynamics methods, including 24 surface hopping models with 8 decoherence corrections and 3 momentum rescaling strategies as well as 6 mean-field models. Then we performed numerical investigations by simulating the photoisomerization of cis-azobenzene combined with on-the-fly electronic structure calculations. Predictions of the S1 lifetime and the quantum yield of the photoproduct using different models are distinct. Surface hopping is more robust than mean-field in our test system. Moreover, the choice of momentum rescaling methods in surface hopping brings more significant changes than decoherence corrections, while a large discrepancy between simulation results with different mean-field algorithms has been observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1cp01374bDOI Listing
June 2021

Association of Lymphocyte-to-Monocyte Ratio With Survival in Advanced Gastric Cancer Patients Treated With Immune Checkpoint Inhibitor.

Front Oncol 2021 1;11:589022. Epub 2021 Jun 1.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Optimal prognostic biomarkers for patients with gastric cancer who received immune checkpoint inhibitor (ICI) are lacking. Inflammatory markers including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) are easily available. However, its correlation with ICI is unknown in gastric cancer. Here, we evaluated the potential association between LMR, PLR, and SII with clinical outcomes in gastric cancer patients undergoing ICI therapy.

Methods: We examined LMR, PLR, SII at baseline, and 6 (± 2) weeks later in 139 patients received ICI therapy between August 2015 and April 2019 at Peking University Cancer Hospital (Beijing, China). Landmark analysis at 6 weeks was conducted to explore the prognostic value of LMR, PLR, and SII on progress-free survival (PFS), and overall survival (OS). A Cox proportional hazards model was used to compute mortality hazard ratios (HRs) for LMR, adjusting for potential confounders including age, sex, ECOG, tumor location, tumor differentiation, tumor stage, line of therapy, and type of anti-PD-1/PD-L1 therapy.

Results: Among 139 patients, 103 (74.1%) were male, median age was 60 years. Median duration of therapy was 6 cycles. We observed that both LMR at baseline and week 6 were independent prognostic factors. Patients with a higher LMR (≥ 3.5) at baseline or week 6 had superior PFS [baseline: HR 0.58, 95% confidence interval (CI): 0.38-0.91; week 6: HR 0.48, 95% CI: 0.29-0.78] and OS (baseline: HR 0.38, 95% CI: 0.24-0.62; week 6: HR 0.52, 95% CI: 0.31-0.88) compared with patients with a lower LMR (< 3.5). Furthermore, for patients with both LMR ≥ 3.5 at baseline and LMR ≥ 3.5 at week 6 were estimated to have much better PFS (HR 0.41, 95% CI: 0.23-0.72) and OS (HR 0.34, 95% CI: 0.18-0.64) than patients with both LMR < 3.5 at baseline and LMR < 3.5 at week 6.

Conclusions: Baseline and early changes in LMR were strongly associated with survival in gastric cancer patients who received ICI therapy, and may serve to identify patients most likely to benefit from ICI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.589022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203902PMC
June 2021

Dysregulated KRAS gene-signaling axis and abnormal chromatin remodeling drive therapeutic resistance in heterogeneous-sized circulating tumor cells in gastric cancer patients.

Cancer Lett 2021 Oct 11;517:78-87. Epub 2021 Jun 11.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Electronic address:

The mechanism by which heterogeneous-sized circulating tumor cells (CTCs) in gastric cancer (GC) patients are resistant to the targeted therapy and/or chemotherapy remains unclear. This study investigated prognostic value and genomic variations of size-heterogenous CTCs, in an attempt to unravel the molecular mechanisms underlying the therapeutic resistance, which is relevant to poor prognosis in GC. Aneuploid CTCs, detected in 111 advanced GC patients, were categorized into small (≤white blood cell [WBC], 25.54%) and large (>WBC, 74.46%) cells. Pre-treatment patients possessing ≥3 baseline small CTCs with trisomy 8 (CTCs) or ≥6 large multiploid CTCs (CTCs) showed an inferior median progression-free survival. Moreover, the cut-off value of ≥6 CTCs was also an effective prognosticator for poor median overall survival. Single cell-based DNA sequencing of 50 targeted CTCs indicated that CTCs and CTCs harbored distinct gene variations respectively. Mutations in the KRAS and Rap1 pathway were remarkably abundant in CTCs, whereas several unique mutations in the MET/PI3K/AKT pathway and SMARCB1 gene were identified in CTCs. Obtained results suggested that CTCs and CTCs exhibited different mechanisms to therapy resistance and correlated with patients' poor outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.06.002DOI Listing
October 2021

Metal- and Base-Free C(sp)-H Arylsulfonylation of Enamides for Synthesis of ()-β-Amidovinyl Sulfones via the Insertion of Sulfur Dioxide.

Org Lett 2021 Jul 11;23(13):4991-4996. Epub 2021 Jun 11.

Department of Dermatology, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and West China School of Pharmacy, Sichuan University, Chengdu 610041, P.R. China.

A metal- and base-free C(sp)-H direct arylsulfonylation of secondary and tertiary enamides with aryldiazonium salts and ex situ generated SO (from SOgen) is presented. This method runs smoothly to produce β-amidovinyl sulfones with excellent stereoselectivities in moderate to excellent yields. Moreover, this strategy features good functional group tolerance and environmentally benign reaction conditions. Mechanistic experiments indicate that this sulfonylation may proceed in a radical pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.1c01419DOI Listing
July 2021

USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bβ via deubiquitinating EGLN3.

J Biomed Sci 2021 Jun 10;28(1):44. Epub 2021 Jun 10.

Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/Clinical College of The Affiliated Central Hospital of Lishui University, Lishui, 323000, China.

Background: Cholangiocarcinoma represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades. Cholangiocarcinoma silent nature limits early diagnosis and prevents efficient treatment.

Methods: Immunoblotting and immunohistochemistry were used to assess the expression profiling of USP9X and EGLN3 in cholangiocarcinoma patients. ShRNA was used to silence gene expression. Cell apoptosis, cell cycle, CCK8, clone formation, shRNA interference and xenograft mouse model were used to explore biological function of USP9X and EGLN3. The underlying molecular mechanism of USP9X in cholangiocarcinoma was determined by immunoblotting, co-immunoprecipitation and quantitative real time PCR (qPCR).

Results: Here we demonstrated that USP9X is downregulated in cholangiocarcinoma which contributes to tumorigenesis. The expression of USP9X in cholangiocarcinoma inhibited cell proliferation and colony formation in vitro as well as xenograft tumorigenicity in vivo. Clinical data demonstrated that expression levels of USP9X were positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that USP9X was involved in the deubiquitination of EGLN3, a member of 2-oxoglutarate and iron-dependent dioxygenases. USP9X elicited tumor suppressor role by preventing degradation of EGLN3. Importantly, knockdown of EGLN3 impaired USP9X-mediated suppression of proliferation. USP9X positively regulated the expression level of apoptosis pathway genes de through EGLN3 thus involved in apoptosis of cholangiocarcinoma.

Conclusion: These findings help to understand that USP9X alleviates the malignant potential of cholangiocarcinoma through upregulation of EGLN3. Consequently, we provide novel insight into that USP9X is a potential biomarker or serves as a therapeutic or diagnostic target for cholangiocarcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12929-021-00738-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191029PMC
June 2021

Clinicopathological features and lymph node and distant metastasis patterns in patients with gastroenteropancreatic mixed neuroendocrine-non-neuroendocrine neoplasm.

Cancer Med 2021 Jul 10;10(14):4855-4863. Epub 2021 Jun 10.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, China.

Objective: Owing to its rarity and heterogeneity, the biological behavior and optimal therapeutic management of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) have not been established. Herein, we aimed to evaluate the clinicopathological characteristics and metastatic patterns of MiNEN.

Methods: Continuous clinicopathological data of MiNEN patients treated at our hospital were retrospectively collected and analyzed.

Results: This study had enrolled 169 patients since January 2010 to January 2020. Pathological components were assessed in 129 patients with MiNEN (76.3%), and a focal (non-)neuroendocrine component was observed in 40 patients (23.7%; <30% of the tumor). Among the enrolled patients, 80 underwent surgical removal of the primary tumor and lymph nodes (LNs), and 34 with distant metastasis underwent biopsy of both primary tumor and metastatic lesions. In patients with LN metastasis, 68.8% (55/80) exhibited a pure component of either neuroendocrine (NE) or adenocarcinoma/squamous carcinoma (AS) in metastatic LNs, while 20% (16/80) showed different components in different LNs, and only 11.2% (9/80) exhibited both NE and AS components in the same LN. In patients with distant metastases, 26.5% (9/34) possessed coexisting NE and AS components in the distant metastases, 70.6% (24/34) were regarded as a pure NE component, and 2.9% (1/34) were comprised of a pure AS component.

Conclusion: Lymph node and distant metastases exhibited distinct metastatic patterns in patients with MiNEN. The major pathological component in regional LNs may have influenced the proportion of the two components within the primary tumor, but distant metastases were dominated by the NE component.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.4031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290235PMC
July 2021

First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.

Lancet 2021 07 5;398(10294):27-40. Epub 2021 Jun 5.

Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.

Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.

Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.

Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.

Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)00797-2DOI Listing
July 2021

Over-expression of SlWRKY46 in tomato plants increases susceptibility to Botrytis cinerea by modulating ROS homeostasis and SA and JA signaling pathways.

Plant Physiol Biochem 2021 May 27;166:1-9. Epub 2021 May 27.

College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China. Electronic address:

WRKY, as one of the largest families of transcription factors (TFs), binds to cis-acting elements of downstream genes to regulate biotic and abiotic stress. However, the role of SlWRKY46 in fungal disease response induced by Botrytis cinerea (B.cinerea) and potential mechanism remains obscure. To ascertain the role of SlWRKY46 in response to B.cinerea, we constructed SlWRKY46-overexpression plants, which were then inoculated with B.cinerea. SlWRKY46-overexpression plants were more susceptible to B.cinerea and accompanied by the inhibited activities of phenylalanine ammonialyase (PAL), polyphenol oxidase (PPO), chitinase (CHI), and β-1,3-glucanase (GLU). Additionally, SlWRKY46-overexpression plants showed the decreased activities of ascorbate peroxidase (APX), superoxide dismutase (SOD) and the content of HO, and the increased content of O. Moreover, over-expression of SlWRKY46 suppressed the salicylic acid (SA) and jasmonic acid (JA) marker genes, pathogenesis related protein (PR1), and proteinase inhibitors (PI Ⅰ and PI Ⅱ) and consequently aggravated the disease symptoms. Therefore, we speculated that SlWRKY46 played negative regulatory roles in B. cinerea infection probably by inhibiting the activities of antioxidants and disease resistance enzymes, regulating SA and JA signaling pathways and modulating reactive oxygen (ROS) homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plaphy.2021.05.021DOI Listing
May 2021

Long-Term Observation and Sequencing Analysis of SKPs-Derived Corneal Endothelial Cell-Like Cells for Treating Corneal Endothelial Dysfunction.

Cell Transplant 2021 Jan-Dec;30:9636897211017830

Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, China.

Corneal endothelial dysfunction is a principal cause of visual deficiency. Corneal transplantation is the most effective treatment for corneal endothelial dysfunction. However, a severe shortage of available donor corneas or human corneal endothelial cells (HCECs) remains a global challenge. Previously, we acquired corneal endothelial cell-like cells (CEC-like cells) derived from human skin-derived precursors (SKPs). CEC-like cells were injected into rabbit and monkey corneal endothelial dysfunction models and exerted excellent therapeutic effect. In this study, we prolonged the clinical observation in the monkey experiment for 2 years. Polymerase chain reaction (PCR) and DNA sequencing were carried out to confirm the existence of CEC-like cells. Histological examinations were carried out to show the corneal morphology. Further transcriptome sequencing was also carried out on HCEC, CEC-like cells before transplantation and after transplantation. We found that the monkeys cornea remained transparent and normal thickness. The total endothelial cell density decreased gradually, but tended to be stable and remained in a normal range during 2-year observation. The CEC-like cells persist during observation and could adapt to the microenvironment after transplantation. The gene expression pattern of CEC-like cells was similar to HCEC and changed slightly after transplantation. In conclusion, this study presented a brand-new insight into CEC-like cells and further provided a promising prospect of cell-based therapy for corneal endothelial dysfunction. The renewable cell source, novel derivation method and simple treatment strategy may be clinically applied in regenerative medicine in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/09636897211017830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182626PMC
May 2021

Impact of Telemedicine Modalities on Equitable Access to Ambulatory Gastroenterology Care.

Gastroenterology 2021 May 26. Epub 2021 May 26.

Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2021.05.042DOI Listing
May 2021

Glutathione-responsive PLGA nanocomplex for dual delivery of doxorubicin and curcumin to overcome tumor multidrug resistance.

Nanomedicine (Lond) 2021 07 28;16(16):1411-1427. Epub 2021 May 28.

Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science & Technology Medical Center, Shenzhen 518036, PR China.

This work aims to develop an injectable nano-drug delivery system to overcome tumor multidrug resistance (MDR). A drug delivery nanoplatform based on PEGylated PLGA with glutathione (GSH) responsivity was constructed for dual delivery of doxorubicin and curcumin (termed DCNP), and its MDR reversal efficiency was studied and . The DCNPs exhibited a rapid drug release profile under high GSH concentration and could enhance the cellular uptake and cytotoxicity of doxorubicin to MDR cancer cells. Moreover, the DCNPs showed better biocompatibility, longer blood circulation and enhanced antitumor efficiency compared with free drugs. The GSH-responsive nanocarrier is believed to be a promising candidate for overcoming tumor MDR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/nnm-2021-0100DOI Listing
July 2021

PTCH1 mutation promotes antitumor immunity and the response to immune checkpoint inhibitors in colorectal cancer patients.

Cancer Immunol Immunother 2021 May 24. Epub 2021 May 24.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.

Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling. In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28.6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0.017). In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0.037; HR, 0.208) and overall survival (OS, P = 0.045; HR, 0.185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0.022; HR, 0.290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors. Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle. Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden. Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-021-02966-9DOI Listing
May 2021

The loss of RNA N-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8 T cell dysfunction and tumor growth.

Cancer Cell 2021 Jul 20;39(7):945-957.e10. Epub 2021 May 20.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China; College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; China National Center for Bioinformation, Beijing, 100101, China. Electronic address:

Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q TAMs are regulated by an RNA N-methyladenosine (mA) program and modulate tumor-infiltrating CD8 T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an mA methyltransferase Mettl14 drives CD8 T cell differentiation along a dysfunctional trajectory, impairing CD8 T cells to eliminate tumors. Mettl14-deficient C1q TAMs show a decreased mA abundance on and a higher level of transcripts of Ebi3, a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8 T cells and overcomes immunosuppressive impact in mice. We show that the METTL14-mA levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an mA methyltransferase in TAMs promotes CD8 T cell dysfunction and tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.04.016DOI Listing
July 2021

A Quality Improvement Intervention Leveraging a Safety Net Model for Surveillance Colonoscopy Completion.

Am J Med Qual 2021 May 18. Epub 2021 May 18.

Department of Quality and Safety, Brigham & Women's Hospital, Harvard Medical School, Boston, MA Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA Division of Gastroenterology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA Division of General Internal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA Department of Quality and Patient Experience, Mass General Brigham, Boston, MA.

Systems to address follow-up testing of clinically positive surveillance colonoscopy results are lacking. The impact of an ambulatory safety net (ASN) intervention on rates of colonoscopy completion was assessed. The ASN team identified patients using an electronic registry, conducted patient outreach, coordinated care, and tracked colonoscopy completion. In all, 701 patients were captured in the ASN program: 58.1% (407/701) had possible barriers to follow-up colonoscopy completion, with rates of 80.1% (236/294) if no barrier, and 40.9% (287/701) overall. Colonoscopy completion likelihood increased with prior polypectomy (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3), and decreased with White race (OR, 0.5; 95% CI, 0.3-0.9), increased inpatient visits (OR, 0.6; 95% CI, 0.4-0.9), more outreach attempts (OR, 0.6; 95% CI, 0.5-0.7), and fair/poor/inadequate preparation (OR, 0.4; 95% CI, 0.2-0.7) in logistic regression models. An ASN model for quality improvement promotes colonoscopy completion rates and identifies patient barriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.JMQ.0000743680.01321.2bDOI Listing
May 2021
-->