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Background: Patients with hemorrhagic stroke have high mortality and disability rates. Nevertheless, early rehabilitation interventions can improve their outcomes. We aimed to apply capsaicin atomization as early intervention to patients with hemorrhagic stroke and explore improvements in cough and swallowing functions. Method: Patients with hemorrhagic stroke were randomly divided into the control group, which received routine care, and the intervention group, which underwent the capsaicin solution nebulization scheme in addition to routine care. Differences in the presence/absence of cough reflex and number of coughs in response to capsaicin, the presence/absence of swallowing reflex in response to water, the presence/absence of postswallow residue, substance P (SP) concentration, and pulmonary inflammation between the two groups were determined before and after the intervention. Results: A total of 53 patients with hemorrhagic stroke were included. Results showed no statistically significant difference in cough reflex in both groups after the intervention ( p > .05). The degree of cough in the intervention group was stronger than that in the control group ( p = .046). No statistically significant difference was observed in the number of patients with swallowing reflex in response to water between the groups ( p > .05). The presence/absence of postswallow residue of the intervention group was stronger than that of the control group ( p = .032). No statistically significant difference was observed between the Glasgow Coma Scale scores of the groups after the intervention ( p > .05). SP in the intervention group was significantly increased ( p = .031). The Clinical Pulmonary Infection Score was significantly lower in the control group, and the difference was statistically significant ( p = .028). Conclusions: Capsaicin nebulization can help enhance the number of coughs in response to capsaicin, reduce postswallow residue, and increase the level of SP in patients with hemorrhagic stroke and has a positive effect on pulmonary inflammation. This study provides intervention points for cough and swallowing rehabilitation after a hemorrhagic stroke. Supplemental Material: https://doi.org/10.23641/asha.21956903

One of the major reasons for poor cancer outcomes is the existence of cancer stem cells (CSCs). CSCs are a small subpopulation of tumor cells that can self-renew, differentiate into the majority of tumor cells, and maintain tumorigenicity. As CSCs are resistant to traditional chemotherapy and radiation, they contribute to metastasis and relapse. Thus, new approaches are needed to target and eliminate CSCs. Here, we sought to target and reduce the frequency of CSCs in melanoma by therapeutic vaccination against CSC-associated transcription factors, such as Sox2 and Nanog, and aldehyde dehydrogenase (ALDH). Toward this goal, we have identified novel immunogenic peptide epitopes derived from CSC-associated Sox2 and Nanog and synthesized synthetic high-density lipoprotein (sHDL) nanodisc vaccine formulated with Sox2, Nanog, and ALDH antigen peptides together with CpG, a Toll-like receptor 9 agonist. Vaccination with nanodiscs containing six CSC antigen peptides elicited robust T cell responses against CSC-associated antigens and promoted intratumoral infiltration of CD8+ T cells, while reducing the frequency of CSCs and CD4+ regulatory T cells within melanoma tumors. Nanodisc vaccination effectively reduced tumor growth and significantly extended animal survival without toxicity toward normal stem cells. Overall, our therapeutic strategy against CSCs represents a cost-effective, safe, and versatile approach that may be applied to melanoma and other cancer types, as well as serve as a critical component in combined therapies to target and eliminate CSCs.

Fasting blood glucose (FBG) variability may make an impact on adverse events in patients with diabetes mellitus. However, the association between long-term changes in FBG and cancer remains unclear. We aimed to investigate this association in a large-scale longitudinal study.Data were collected from 46 761 patients with type 2 diabetes mellitus aged 20-80 years who participated in the Diabetes Standardized Management Program in Shanghai, China. We adopted four indicators, including standard deviation (SD), coefficient of variation (CV), variation independent of the mean (VIM), and average real variability (ARV) to describe FBG variability. Adjusted multivariable Cox regression analyses and restricted cubic splines were used to investigate the association between long-term FBG variability and cancer risk. We also determined the interactive effect of FBG variability with hypertension and FBG-mean with hypertension on cancer risk, respectively.In this study, we confirmed 2218 cancer cases (51.1% male) over a median follow-up of 2.86 years. In the multivariable-adjusted models, participants in the highest quartile of FBG variability had an increased risk of cancer compared with those in the lowest quartile. The nonlinear association was found when using FBG-VIM, FBG-ARV, and FBG-SD in restricted cubic spline plots. There was a significant interaction effect of FBG variability with hypertension on cancer, whereas the effect of FBG-mean with hypertension did not attain significance.Our retrospective cohort study demonstrated a positive association between the long-term changes in FBG and cancer risk in patients with type 2 diabetes mellitus. FBG variability may independently predict cancer incidence.背景: 空腹血糖(FBG)变异性可能对糖尿病患者的不良事件产生影响。然而，空腹血糖的长期变化与癌症之间的联系仍不清楚。本研究旨在一项大规模纵向研究中调查和量化这种关联。 方法: 对参加中国上海市糖尿病标准化管理项目的46,761例年龄在20到80岁的2型糖尿病患者进行调查。我们采用标准差(SD)、变异系数(CV)、独立于均值的变异(VIM)和平均实际变异(ARV)4个指标来描述FBG的变异性。调整后的多变量COX回归分析和限制三次样条法被用来调查长期空腹血糖(FBG)变异性与癌症风险之间的关系。我们还分别确定了空腹血糖变异性与高血压和空腹血糖均值与高血压之间的交互作用对癌症风险的影响。 结果: 在这项研究中，我们确认了2218例癌症病例(51.1%为男性)，平均随访时间为2.86年。在多变量校正模型中，FBG变异性最高四分位的参与者比那些最低四分位数的参与者患癌症的风险更高。在限制三次样条图中使用FBG-VIM、FBG-ARV和FBG-SD时，发现了非线性关联。FBG变异性与高血压之间存在显著的交互作用，而FBG均值与高血压之间的交互作用不显著。 结论: 我们的回顾性队列研究显示，FBG的长期变化与2型糖尿病患者的癌症风险呈正相关。FBG变异性可独立预测癌症发病率。.

The present meta-analysis was updated with randomized controlled trials (RCTs) to revaluate the efficacy and safety of cetuximab vs. cisplatin combined with radiotherapy in patients of head and neck squamous cell carcinoma (HNSCC).A meta-analysis containing RCTs that compared the efficacy or toxicity of cetuximab and cisplatin in HNSCC patients was conducted.Seven RCTs were included in the final analysis. The patients treated by cetuximab plus radiotherapy showed an inferior overall survival (OS) and locoregional control (LRC) compared to cisplatin plus radiotherapy. The tendency of progression-free survival (PFS) was in agreement with OS and LRC. Subgroup analysis showed that cetuximab had poorer OS relative to cisplatin in the absence of induction chemotherapy. The profile of severe adverse events (SAEs) varied between the two groups, no significant difference in total SAEs was shown for the two arms.Cetuximab combined with radiotherapy shows significantly reduced therapeutic efficacy compared to cisplatin plus radiotherapy in HNSCC patients.

Purpose: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. Results: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). Conclusions: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

Recent years there have been witnessed considerable advances in endoscopic selective lateral neck dissection (LND). However, dissection of lymph nodes at level IV and level VI via the chest approach is inherently challenging. In this study, we used combined trans-oral and chest approach for endoscopic thyroidectomy in patients with cT1-2N1bM0 papillary thyroid carcinoma (PTC).Clinical characteristics and surgical outcomes of ten patients with cT1-2N1bM0 PTC who underwent endoscopic thyroidectomy via combination of trans-oral and chest approach between September 2020 and September 2021 were retrospectively reviewed.All 10 patients successfully underwent total thyroidectomy and selective LND via chest approach, while central neck dissection (CND) and supplementary dissection of lymph nodes at level IV were performed via the trans-oral approach. The mean number of positive/retrieved level II, III-IV, and VI lymph nodes were 0.6 ± 1.0/9.8 ± 5.0, 4.6 ± 2.8/23.1 ± 4.7, and 4.9 ± 3.4/10.3 ± 4.6, respectively. Four patients developed transient hypoparathyroidism which spontaneously resolved within 1 month. Five patients developed numbness of lateral neck and ear and one patient experienced limb lift restriction. No other complications or tumor recurrence occurred during follow-up.It is feasible to perform total thyroidectomy, CND, and selective LND via combined trans-oral and chest approach, and satisfactory short-term outcomes were observed in this cohort. This approach may offer one more option for cT1-2N1bM0 PTC patients, especially those in whom metastatic lymph nodes at level IV or level VI are detected by preoperative examination.

The analyses of the LHCb data on $X(6900)$ found in di-$J/\psi$ and $J/\psi \psi(3686)$ systems are performed using a momentum-dependent {Flatt\'{e}}-like parameterization. The use of the pole counting rule and spectral density function sum rule give consistent conclusions that $X(6900)$ may not be a molecule of $J/\psi \psi(3686)$. Nevertheless it is still possible that $X(6900)$ be a molecule of higher states, such as $J/\psi\psi(3770)$, $\chi_{c0}\chi_{c2}$, etc., Comment: 7pages with 9 figures

This study conducts a series of undrained cyclic shear tests on saturated coral sand with different initial relative densities (Dr) subjected to a 90° jump rotation of the principal stress with various initial orientations. Considering liquefiable coral sand as a fluid, an important finding is that the variation in the apparent viscosity with the number of cycles is significantly affected by Dr, the effective mean principal stress (p0'), cyclic stress ratio, cyclic loading path, and cyclic loading frequency. The average flow coefficient (κ) is introduced to describe the fluidity of saturated coral sand under cyclic loading by considering the variation in the shape of the stress-strain rate curve. A positive exponential correlation is observed between κ and the excess pore water pressure ratio (ru) under the given cyclic loading modes. Another significant finding is that the solid-liquid phase change time is the turning point of the apparent viscosity and the average flow coefficient gradients with ru. The inversion point’s excess pore water pressure ratio is approximately 0.9, defined as the excess pore water pressure ratio during the solid-liquid phase transformation (ruth). The ruth value is not affected by cyclic loading mode, p0', and Dr.

Supplementary Table from Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial

Purpose:This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Patients and Methods:In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety.Results:Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%).Conclusions:Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

Supplementary Data from Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial

Previous studies have suggested that a low albumin-to-alkaline phosphatase ratio (AAPR) is associated with a lower survival rate in patients with various malignancies. However, the relationship between pretreatment AAPR and the prognosis of patients with gastric cancer (GC) remains unclear.To investigate the prognostic value of AAPR in distant metastatic GC.A total of 191 patients with distant metastatic cancer from a single institute were enrolled in this study. Pretreatment clinical data, including serum albumin and alkaline phosphatase levels, were collected. A chi-square test or Fisher's exact test was applied to evaluate the correlations between AAPR and various clinical parameters in GC patients. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate the prognostic efficacy of AAPR in metastatic GC patients. A two-sidedA receiver operating characteristic curve indicated that 0.48 was the optimal threshold value for AAPR. AAPR ≤ 0.48 was significantly associated with bone (Pretreatment AAPR may serve as an independent prognostic factor for predicting PFS and OS in patients with metastatic GC. Furthermore, AAPR may assist clinicians with individualizing treatment.

Primary lymphoma of the female genital tract (PLFGT) is a sporadic extranodal lymphoma. Its epidemiology and prognosis are not fully recognized. Our study aimed to construct and validate prognostic nomograms for predicting survival for patients with PLFGT.Incidence rate from 1975 to 2017 and patients with PLFGT from 1975 to 2011 in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively reviewed. The nomograms of overall survival (OS) and disease-specific survival (DSS) were established according to the multivariate Cox regression analyses. The concordance index (C-index) and calibration plots were used to demonstrate its robustness and accuracy.A total of 617 PLFGT patients were identified. The overall incidence of PLFGT is 0.437/1,000,000 (adjusted to the US standard population in 2000) from 1975 to 2017. Age, histological subtype, Ann Arbor Stage, and therapeutic strategy were identified as independent prognostic factors for OS and DSS by multivariate Cox regression (The incidence of PLFGT has increased in the past 40 years, and the nomograms were developed and validated as an individualized tool to predict OS and DSS for all PLFGT patients and DLBCL patients. All patients are divided into three risk groups to assist clinicians to identify patients at high-risk and choose the optimal individualized treatments for patients.HighlightsThe incident of PLFGT and its subtypes were calculated and compared.Nomograms were constructed to predict the 1-, 5-, and 10-year OS and DSS.Patients are divided into the low-risk, medium-risk, and high-risk according total score of the nomogram.

To identify the tumor factors of in-field failure for nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era.Patterns of recurrence were classified as in-field, marginal, and out-field failures. Multivariate analyses with the Cox proportional hazards model were used to identify tumor-related factors of in-field failure.A total of 1039 patients with NPC received IMRT from 2012 to 2019 and 75 developed recurrences, with 88.0% (66/75) considered as having in-field failures. Multivariate analysis showed that pretreatment gross tumor volume of nasopharynx ≥68.8 mL and histopathological type of nonkeratinizing differentiated carcinoma (NKDC) were the independent tumor factors of in-field local failure, while gross tumor volume of involved lymph nodes ≥19.9 mL and cervical nodal necrosis (CNN) were associated with in-field regional failure (all p 0.05).In-field failure was the major pattern of recurrence in patients with NPC. Large tumor volume, NKDC, and CNN were the tumor factors associated with in-field failure.

A simple protocol for the rapid synthesis of chalcogen-containing compounds by an I2O5-promoted oxidative Csp2–H selenation and seleno/thiocyanation of activated arenes is reported here.

To evaluate the long-term outcome and prognostic factors of patients with nasopharyngeal carcinoma (NPC) from low-endemic regions of China who received definitive intensity-modulated radiation therapy (IMRT). The clinical data from 608 patients with newly-diagnosed non-metastatic NPC who have received initial treatment at our cancer center from January, 2008 to December, 2013 were retrospectively reviewed. All patients received definitive IMRT, and 87.7% received platinum-based chemotherapy. The median follow-up duration was 51 months (follow-up rate, 98.5%; range, 10–106 months) for the entire cohort. The 5-year overall survival rate was 79.7%. The 5-year local relapse-free survival rate, regional relapse-free survival rate, distant metastasis-free survival rate and progression-free survival rate were 92.4%, 93.3%, 79.2% and 74.3%, respectively. A total of 153 patients had experienced treatment failure, with distant metastasis as the primary cause in 77.1% (118/153). Patients with T4 or N3 diseases had a significantly poorer prognosis than other subcategories. Stage T4 and N3 were closely associated with distant metastasis, with the metastatic rate of 29.3% and 45.5%, respectively. IMRT provides patients with non-metastatic NPC with satisfactory long-term survival. Both T stage and N stage are important prognostic factors for NPC patients. Patients with T4 or N3 diseases have significantly increased distant metastatic rates and poor survival time.

Background Endoscopic thyroidectomy is widely performed as it does not result in neck scar. However, there is a paucity of reports pertaining to completely endoscopic lateral neck dissection (LND). In this study, we introduce our step-wise approach for performing endoscopic selective LND via the chest–breast approach. We refer to this approach as Qin’s seven steps. Methods The Qin’s seven steps are: (1) establishment of working space range; (2) dissection of lymph nodes between the SCM and the sternohyoid muscle (level IV) and exposure of omohyoid; (3) dissection of lymph nodes at level IV; (4) dissection of lymph nodes at level III; (5) dissection of lymph nodes at carotid triangle (level III); (6) exposure of accessory nerve and dissection of lymph nodes at level II a; (7) dissection of lymph nodes at level II b. We reviewed the clinical data of 35 patients with papillary thyroid cancer (PTC) who were operated using the Qin’s seven steps. Results All 35 patients successfully underwent LND; bilateral LND was performed in 5 patients. The mean tumor size was 1.8 ± 1.0 cm; seven patients had multiple lesions. The mean number of retrieved lymph nodes in level II, III and IV were 8.8 ± 5.6, 6.1 ± 4.0 and 9.3 ± 5.1, respectively. As for complications, there were 3 cases of accessory nerve injury and 1 case of hypoglossal nerve injury. Internal jugular vein injury, cervical plexus injury and lymphatic leakage occurred in 2, 7, and 1 patients, respectively. Conclusion The Qin’s seven steps for performing endoscopic selective LND could be safely used in PTC patients with lateral lymph node metastasis. Satisfactory results were achieved in the short-term follow-up period. We recommend the use of Qin’s seven steps for PTC patients who are not desirous of neck scar.

While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC.pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled.Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy.Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.

Background This study aimed to evaluate the feasibility and safety of the trans-oral endoscopic thyroidectomy vestibular approach (TOETVA) with neuroprotection techniques for the surgical management of papillary thyroid carcinoma (PTC). Methods Patients with PTC who underwent TOETVA between December 2016 and July 2020 were included in this study, and their relevant clinical characteristics, operational details, and surgical outcomes were reviewed and extracted from their medical records for further analysis. Results A total of 75 patients successfully underwent TOETVA with zero conversions. Unilateral lobectomy with isthmectomy and total thyroidectomy were completed for 58 and 17 patients, respectively, all using our unique neuroprotective procedure and ipsilateral central neck dissection (CND). The mean number of retrieved lymph nodes versus positive lymph nodes was 6.8 ± 3.7 vs. 1.5 ± 2.3. Postoperative complications included three cases of transient superior laryngeal nerve (SLN) palsy (4.0%), five cases of transient recurrent laryngeal nerve (RLN) palsy (6.7%), 14 cases of transient hypoparathyroidism (18.7%), two cases of numb chin (2.7%) and two cases of flap perforation (2.7%). The follow-up period for patients with PTC lasted for 15.6 ± 10.9 months, during which no other complications or tumor recurrence were observed. Conclusion TOETVA can be safely performed for patients with PTC with satisfactory results during the short-term follow-up period. Our neuroprotection techniques can be integrated into TOETVA, which is worth recommending for PTC patients who desire better cosmetic surgical outcomes.

We have conducted clinical trials for cancer immunotherapy using vaccine-primed lymph node (VPLN) T calls based on our animal studies with tumor-draining lymph node (TDLN) T cells. More recently we have identified antitumor effector TDLN B cells which demonstrated significant tumor reactivity in vitro and therapeutic efficacy in vivo upon adoptive transfer which can be enhanced by anti-PD-L1 administration. It is unknown whether tumor cells, particularly cancer stem cells (CSCs) could suppress the antitumor effector B cells. We found that depletion of B cells with anti-CD20 mAb prior to anti-PD-L1 administration resulted in more aggressive tumor growth, and the anti-tumor efficacy of anti-PD-L1 was significantly reduced in both 4T1 and CT26 murine tumor-bearing hosts, suggesting the involvement of host B cells in the anti-tumor effect of anti-PD-L1. In addition, administration of anti-PD-L1 partially recovered the humoral immune response, confirming the PD-L1/PD-1 pathway involvement in B cell suppression. We detected elevated expression of PD-1 on activated B cells, and higher PD-L1 expression on ALDHhigh CSCs than on ALDHlow non-CSCs. Co-culturing ALDHhigh CSCs with purified B cells significantly reduced IgG secretion, and such CSC-mediated B cell suppression was rescued by adding anti-PD-L1 mAb in a dose-dependent manner to the CSC-B cell co-culture. These experiments thus indicate that CSCs suppress the IgG production by B cells via the PD-L1/PD-1 axis. Tumor cells were recently recognized to suppress T cell function via secretion of exosomes that express PD-L1. To investigate if exosomal PD-L1 contributes to B cell immunosuppression, we generated Rab27ako D5 cells to delete exosomes as well as PD-L1ko D5 cells by CRISPR/Cas9 gene editing. D5-derived exosomes suppressed B cell proliferation and IgG production in vitro, and administration of these exosomes promoted tumor growth and reduced animal survival, revealing the role of tumor-derived exosomes in B cell immunosuppression. Tumor-derived exosomes expressed PD-L1, but PD-L1 was absent in the exosomes isolated from the PD-L1ko tumor cells as evident by western blot and flow cytometry. Deletion of Rab27a or PD-L1 did not affect the proliferation of the tumor cells in vitro. However, Rab27ako or PD-L1ko resulted in significantly enhanced host anti-tumor immunity evident by reduced 4T1 tumor growth in vivo compared with the WT tumor. Importantly, anti-PD-L1 therapy significantly reduced Rab27ako or PD-L1ko 4T1 tumor growth and prolonged animal survival vs. the WT tumor control. We conclude that PD-L1-expresing CSCs and PD-L1-expresing exosomes suppress antitumor effector B cells via the PD-L1/PD-1 axis. To characterize the suppression of CSC-derived exosomes on host B cells as well as T cells, isolation of Rab27ako ALDHhigh CSCs warranties further investigation. Citation Format: Ying Xin, Jiayu Liu, You Qin, Kexing Lyu, Sifei Yu, Ming Lin, Max Wicha, Alfred E. Chang, Qiao Li. Cancer stem cells and exosomal PD-L1 suppress anti-tumor B cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2256.

While perturbative QCD is sufficient for understanding the color, mass and energy dependences of parton energy loss and jet quenching at large transverse momentum in heavy-ion collisions, a simultaneous description of heavy flavor nuclear modification factor $R_\mathrm{AA}$ and elliptic flow coefficient $v_2$ at low and intermediate $p_\mathrm{T}$ still remains a challenge due to the effects from non-perturbative interactions. In this work, we extend the linear Boltzmann transport model by implementing a generalized Cornell-type potential that incorporates both short-range Yukawa interaction and long-range color confining interaction between heavy quarks and the QGP medium. Combining our new approach for heavy-quark-QGP interaction with a (3+1)-dimensional hydrodynamic model CLVisc for the QGP evolution and a hybrid fragmentation-coalescence model for heavy quark hadronization, we obtain a satisfactory description of heavy meson $R_\mathrm{AA}$ and $v_2$ from low to intermediate to high $p_\mathrm{T}$ observed at both RHIC and the LHC. By model-data-comparison, we extract for the first time the in-medium heavy quark potential from open heavy flavor measurements; the result is in agreement with the lattice QCD calculation. Our study indicates that while jet quenching at high $p_\mathrm{T}$ is dominated by perturbative QCD interactions, non-perturbative interactions are indispensible for understanding heavy flavor quenching and flow at low and intermediate $p_\mathrm{T}$., Comment: 9 pages, 5 figures

A series of undrained cyclic axial-torsional shear tests on saturated coral sand and quartz sand under linear, circular, and heart stress paths are performed. The test results show significant diff...

Purpose Stereotactic body radiotherapy (SBRT) may have significant immunomodulatory effects that enhance tumor response to immune checkpoint inhibitors. This phase 2 clinical trial was conducted to evaluate the safety and efficacy of combining palliative SBRT with camrelizumab (an anti-PD1 monoclonal antibody) in patients with unresectable hepatocellular carcinoma (uHCC). Methods Patients with uHCC, Child–Pugh A/B liver function, and at least one measurable lesion were enrolled between April 2020 and August 2022. Patients were administered 200 mg camrelizumab intravenously from the first day of palliative SBRT and then every 3 weeks. Palliative SBRT was delivered daily over five fractions per week, with a dose range of 30–50 Gy. The primary endpoints were objective response rate (ORR) and safety. This trial was registered at ClinicalTrials.gov (NCT04193696). Results Twenty-one patients were enrolled; the median radiation dose was 40 Gy, and the median number of cycles of camrelizumab was five. The ORR was 52.4%. After a median follow-up of 19.7 months, the median progression-free and overall survival were 5.8 and 14.2 months, respectively. The overall survival probability was 85.7% at 6 months, 76.2% at 9 months, and 59.9% at 12 months. All grade 3 treatment-related adverse events (TRAEs) occurred in five patients (23.8%) and were manageable. No grade 4/5 TRAEs were observed. Conclusion Palliative SBRT plus camrelizumab showed promising antitumor activity against uHCC. Toxicities were manageable with no unexpected safety issues. This study provides evidence of a new therapeutic method for the treatment of uHCC.

Recent experiments have observed large anisotropic collective flows in high multiplicity proton-lead collisions at the CERN Large Hadron Collider (LHC), which indicates the possible formation of mini quark-gluon plasma (QGP) in small collision systems. However, no jet quenching has been confirmed in such small systems so far. To understand this intriguing result, the system size scan experiments have been proposed to bridge the gap between large and small systems. In this work, we perform a systematic study on both heavy and light flavor jet quenching in different collision systems at the LHC energies. Using our state-of-the-art jet quenching model, which combines the next-to-leading-order perturbative quantum chromodynamics framework, a linear Boltzmann transport model and the (3+1)-dimensional viscous hydrodynamics simulation, we provide a good description of nuclear modification factor RAA for charged hadrons and D mesons in central and midcentral Pb+Pb and Xe+Xe collisions measured by the CMS collaboration. We further predict the transverse momentum and centrality dependences of RAA for charged hadrons, D and B mesons in Pb+Pb, Xe+Xe, Ar+Ar, and O+O collisions at the LHC energies. Our numerical results show a clear system size dependence for both light and heavy flavor hadron RAA across different collision systems. Sizable jet quenching effect is obtained for both heavy and light flavor hadrons in central O+O collisions at the LHC energies. Our study provides a significant bridge for jet quenching from large to small systems, and should be helpful for finding the smallest QGP droplet and the disappearance of QGP in relativistic nuclear collisions.

The regulatory T cells (Tregs) are a subpopulation of lymphocytes that suppress the immune responses. The prognostic value of Tregs in lymphoma patients remains controversial. Thus, we conducted this meta-analysis to clarify the role of Tregs in the prognosis of lymphoma patients. We searched PubMed, Embase, and Web of Science to obtain eligible studies that evaluated the prognostic factor of Tregs for lymphoma patients. Hazards ratios (HRs) with the matching 95% confidence intervals (95%CIs) were merged to estimate the prognostic value of Tregs. We finally retrieved 23 eligible studies, including a total of 2269 patients. The overall pooled analysis on all types of lymphomas showed that Tregs had a significantly positive association with prolonged overall survival (OS) (HR = 0.633, 95% CI 0.528–0.758) and progression-free survival (PFS) (HR = 0.451, 95% CI 0.261–0.779). Subgroup analysis indicated that high Tregs were significantly correlated with longer OS in Hodgkin lymphoma, diffuse large B cell lymphoma, and natural killer/T cell lymphoma. However, there was no significant association of Tregs with T cell lymphoma and follicular lymphoma. Increased Tregs indicates a better prognosis for patients with lymphoma. Tregs could be used as a valuable prognostic biomarker of lymphoma patients.

Cancer stem cells (CSCs) proliferate extensively and drive tumor metastasis and recurrence. CSCs have been identified in over 20 cancer types to date, but it remains unknown how to target and eliminate CSCs in vivo. Aldehyde dehydrogenase (ALDH) is a marker that has been used extensively for isolating CSCs. Here we present a novel approach to target and reduce the frequency of ALDH(high) CSCs by vaccination against ALDH. We have identified ALDH1-A1 and ALDH1-A3 epitopes from CSCs and developed synthetic high-density lipoprotein nanodiscs for vaccination against ALDH(high) CSCs. Nanodiscs increased antigen trafficking to lymph nodes and generated robust ALDH-specific T cell responses. Nanodisc vaccination against ALDH(high) CSCs combined with anti-PD-L1 therapy exerted potent antitumor efficacy and prolonged animal survival in multiple murine models. Overall, this is the first demonstration of a simple nanovaccine strategy against CSCs and may lead to new avenues for cancer immunotherapy against CSCs.

Exosome-associated liquid biopsies are hampered by challenges in the exosomal quantification and phenotyping. Here, we present a bioinspired exosome-activated DNA molecular machine (ExoADM) with multivalent cyclic amplification that enables highly sensitive detection and phenotyping of circulating exosomes. ExoADM harbors two (an exposed and a hidden) DNA toehold domains that actuate sequential branch migration and multivalent recycling in response to exosomal surface markers. Importantly, this self-powered ExoADM achieves a high sensitivity (33 particles/μL) and is compatible with another DNA nanomachine targeting different exosomal surface markers for dual-color phenotyping. Using this strategy, we can simultaneously track the dynamic changes of ExoPD-L1 and ExoCD63 expression induced by signaling molecules. Further, we found that their expression levels on circulating exosomes could well differentiate cancer patients from the normal individuals. More importantly, ExoPD-L1 levels could reflect the efficacy of different treatments and guide anti-PD-1 immunotherapy, suggesting the potential of ExoPD-L1 in clinical diagnosis and targeted therapy monitoring.

Controversial views regarding the roles of B cells in tumor immunity have existed for several decades. However, more recent studies have focused on its positive properties in antitumor immunity. Many studies have demonstrated a close association of the higher density of intratumoral B cells with favorable outcomes in cancer patients. B cells can interact with T cells as well as follicular dendritic cells within tertiary lymphoid structures, where they undergo a series of biological events, including clonal expansion, somatic hypermutation, class switching, and tumor-specific antibody production, which may trigger antitumor humoral responses. After activation, B cells can function as effector cellsviadirect tumor-killing, antigen-presenting activity, and production of tumor-specific antibodies. At the other extreme, B cells can obtain inhibitory functions by relevant stimuli, converting to regulatory B cells, which serve as an immunosuppressive arm to tumor immunity. Here we summarize our current understanding of the bipolar properties of B cells within the tumor immune microenvironment and propose potential B cell-based immunotherapeutic strategies, which may help promote cancer immunotherapy.

In this study, a series of resonant-column experiments were conducted on marine clays from Bohai Bay and Hangzhou Bay, China. The characteristics of the dynamic shear modulus (G) and damping ratio (D) of these marine clays were examined. It was found that G and D not only vary with shear strain (γ), but they also have a strong connection with soil depth (H) (reflected by the mean effective confining pressure (σm) in the laboratory test conditions). With increasing H (σm) and fixed γ, the value of G gradually increases; conversely, the value of D gradually decreases, and this is accompanied by the weakening of the decay or growth rate. An intelligent model based on a back-propagation neural network (BPNN) was developed for the calculation of these parameters. Compared with existing function models, the proposed intelligent model avoids the forward propagation of data errors and the need for human intervention regarding the fitting parameters. The model can accurately predict the G and D characteristics of marine clays at different H (σm) and the corresponding γ. The prediction accuracy is universal and does not strictly depend on the number of neurons in the hidden layer of the neural network.

The shear modulus is an essential parameter that reflects the mechanical properties of the soil. However, little is known about the shear modulus of coral sand, especially under complex consolidation conditions. In this paper, we present the results of a multi-stage strain-controlled undrained cyclic shear test on saturated coral sand. The influences of several consolidation state parameters: effective mean principal stress (p0′), consolidation ratio (kc), consolidation direction angle (α0), and coefficient of intermediate principal stress (b) on the maximum shear modulus (G0), the reference shear strain (γr) and the reduction of shear modulus (G) have been investigated. For a specified shear strain level, G will increase with increasing p0′ and kc, but decrease with increasing α0 and b. However, the difference between G for various α0 and b can be reduced by the increase of shear strain amplitude (γa). G0 shows an increasing trend with the increase of p0′ and kc; on the contrary, with the increase of α0 and b, G0 shows a decreasing trend. To quantify the effect of consolidation state parameters on G0, a new index (μG0) with four parameters (λ1, λ2, λ3, λ4) which is related to p0′, kc, α0, b is proposed to modify the prediction model of G0 in literature. Similarly, the values of γr under different consolidation conditions are also evaluated comprehensively by the four parameters, and the related index (μγr) is used to predict γr for various consolidation state parameters. A new finding is that there is an identical relationship between normalized shear modulus G/G0 and normalized shear strain γa/γr for various consolidation state parameters and the Davidenkov model can describe the G/G0–γa/γr curves. By using the prediction model proposed in this paper, an excellent prediction of G can be obtained and the deviation between measured and predicted G is all within ±10%.