Colorectal cancer-specific IFNß delivery overcomes dysfunctional dsRNA-mediated type I interferon signaling to increase the abscopal effect of radiotherapy.

BACKGROUND: Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC. METHODS: Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNß1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq. RESULTS: Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8+ immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNß1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models. CONCLUSION: Our results support that increasing cancer-intrinsic IFNß1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.

Prognostic Value of Immune Cells Subsets Within the Tumor Microenvironment in Patients With Rectal Adenocarcinoma.

BACKGROUND/AIM: One-third of newly diagnosed colorectal cancer cases are rectal cancers. Multimodal treatment regimens including surgery, radiotherapy, and chemotherapy improve local control and survival outcome and decrease tumor relapse for patients with rectal adenocarcinoma (READ). However, stratification of patients to predict their responses is urgently needed to improve therapeutic responses. PATIENTS AND METHODS: Immunostainings of CD3+, CD8+, and CD45RO+ immune cell subsets within the tumor microenvironment were evaluated using immunohistochemistry in two hundred seventy-nine READ patients. RESULTS: In this study, we found that examination of the adaptive immune response by quantifying CD3+, CD8+, and CD45RO+ immune cell subsets, provides improved and independent prognostic value for patients with READ. Regardless of conventional clinical and pathologic parameters, the densities of T cell subsets were strongly related to a better prognosis in patients with READ. High density of intratumoral immune cells is associated with absence of nodal metastasis, lymphovascular invasion, and perineural invasion. Moreover, high tumor-infiltrating lymphocyte (TIL) subsets were associated with favorable survival outcome in patients with READ, especially high-risk patients with advanced READ. CONCLUSION: Immune cell subsets including CD3, CD8, and CD45RO within the tumor microenvironment were independent prognostic factors for patients with READ.

Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma.

Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells in vitro and in vivo. Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.

TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer.

ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1 cleavage via a caspase 8/3-dependent pathway to enhance cancer cell immunogenicity, leading to dendritic cell maturation and T-cell activation. Blockade of the ATP receptor P2RX7 by the systemic administration of small molecules significantly attenuated the therapeutic efficacy of chemotherapy and decreased the infiltration of immune cells. In contrast, administration of an ATP mimic markedly increased the therapeutic efficacy of chemotherapy and enhanced the infiltration of immune cells in vivo. High PANX1 expression was positively correlated with the recruitment of DCs and T cells within the tumor microenvironment and was associated with favorable survival outcomes in CRC patients who received adjuvant chemotherapy. Furthermore, a loss-of-function P2RX7 mutation was associated with reduced infiltration of CD8+ immune cells and poor survival outcomes in patients. Taken together, these results reveal that TNFα-mediated PANX1 cleavage promotes ATP-P2RX7 signaling and is a key determinant of chemotherapy-induced antitumor immunity.

Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer.

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II-III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1-TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063-2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.

Impact of Pattern Recognition Receptors on the Prognosis of Chemotherapy-treated Rectal Cancer Patients.

BACKGROUND/AIM: Chemotherapeutic drugs or radiation can cause immunogenic cell death (ICD) and damage-associated molecular pattern (DAMP) release to activate pattern recognition receptor (PRR) in immune cells. Several PRRs bridge innate immunity and adaptive immunity and are implicated in the anticancer immune response. However, single nucleotide polymorphisms (SNPs) in PRRs are associated with chemotherapeutic drugs or radiation response in cancer treatment. PATIENTS AND METHODS: We enrolled 117 patients with rectal cancer who received surgery with or without postoperative chemotherapy and examined the SNPs in PRRs from formalin-fixed, paraffin embedded tissues. The genotypes of RAGE (G82S/rs2070600), P2RX7 (E496A/rs3751143), and FPR1 (E346A/rs867228) were determined and analyzed using the MassARRAY platform. RESULTS: We integrated the status of PRR polymorphism into the PRR score and found that the PRR score was significantly associated with 10-year disease-free survival (DFS) (p=0.025) in patients with rectal cancer. Moreover, the PRR score was an independent risk factor for 10-year DFS (HR=4.400, 95%CI=1.607-12.212, p=0.004) and 10-year overall survival (OS) (HR=4.674, 95%CI=1.423-16.038, p=0.011) in patients with rectal cancer treated postoperatively with adjuvant chemotherapy. CONCLUSION: The PRR score is an independent prognostic factor for the survival outcome of patients with rectal cancer, especially those treated postoperatively with adjuvant chemotherapy. PRR score evaluation may be used as a biomarker in the clinic.

Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation.

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084-1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103-1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.

PBDB-T-Based Binary-OSCs Achieving over 15.83% Efficiency via End-Group Functionalization and Alkyl-Chain Engineering of Quinoxaline-Containing Non-Fullerene Acceptors.

Molecular backbone modification, alkyl-chain engineering, and end-group functionalization are promising strategies for developing efficient high-performance non-fullerene acceptors (NFAs). Herein, two new NFAs, named TPQ-eC7-4F and TPQ-eC7-4Cl, are designed and synthesized. Both molecules have linear octyl chains on fused quinoxaline-containing heterocyclics as the central backbone and difluorinated (2F)/dichlorinated (2Cl) 1,1-dicyanomethylene-3-indanone (IC) as the end-group units. The influences of alkyl-chains on fused quinoxaline backbone and different halogenated end-groups on optical, electrochemical, and photovoltaic performances of organic solar cells (OSCs) are studied. In comparison with TPQ-eC7-4Cl, TPQ-eC7-4F exhibits blue-shifted absorptions with higher molar extinction coefficients in the film state as well as in the donor/acceptor (D/A) blend film state and up-shifting lowest unoccupied molecular orbital (LUMO) energy level. As a result, the OSC devices based on the PBDB-T:TPQ-eC7-4F display an outstanding power conversion efficiency (PCE) of 15.83% with a simultaneously increased open-circuit voltage (Voc) of 0.85 V, a short-circuit current-density (Jsc) of 25.89 mA cm-2, and a fill factor (FF) of 72.20%, whereas the PBDB-T:TPQ-eC7-4Cl-based OSC device shows a decent PCE of 14.48% with a Voc of 0.84 V, a Jsc of 24.56 mA/cm2, and an FF of 69.77%. To the best of our knowledge, this is the highest photovoltaic performance of PBDB-T-based single-junction binary-OSCs. In comparison, ascribed to the high crystallinity and low solubility of BTP-eC7-4Cl, the corresponding PBDB-T:BTP-eC7-4Cl-based OSC device shows poor photovoltaic performance (PCE of 11.87%). The experimental results demonstrate that fine-tuning the fused quinoxaline backbone with alkyl-chain and end-group functionalization are promising strategies to construct high-performance NFAs for PBDB-T-based single-junction binary-OSCs.

Engineered sTRAIL-armed MSCs overcome STING deficiency to enhance the therapeutic efficacy of radiotherapy for immune checkpoint blockade.

Radiotherapy (RT) mainly elicits antitumor immunity via the cGAS/STING axis for type I interferon (IFN) production. However, dysregulation of cGAS/STING constrains radiotherapy-induced antitumor immunity and type I IFN-dependent cell death and is associated with shorter survival of patients with colorectal cancer (CRC). Due to their tumor tropism, mesenchymal stem cells (MSCs) have shown the potential to deliver therapeutic genes for cancer therapy. Here, we showed that MSCs enhance the sensitivity to RT by inducing TRAIL-dependent cell death and remodel the tumor microenvironment by recruiting CD8+ immune cells to upregulate PD-L1 in the tumor. By engineering MSCs to express CRC-specific soluble TRAIL via adenovirus-associated virus 2 (AAV2), we found that the therapeutic activity of MSC-sTRAIL was superior to that of MSCs alone when combined with RT. Combined treatment with MSC-sTRAIL and RT significantly reduced cell viability and increased apoptosis by inducing TRAIL-dependent cell death in STING-deficient colorectal cancer cells. MSC-sTRAIL directly triggered TRAIL-dependent cell death to overcome the deficiency of the cGAS/STING axis. Moreover, these combination treatments of MSC-sTRAIL and RT significantly remodeled the tumor microenvironment, which was more suitable for anti-PD-L1 immunotherapy. Taken together, this therapeutic strategy represents a novel targeted treatment option for patients with colorectal cancer, especially cGAS/STING-deficient patients.

Prognostic and clinical significance of subcellular CDC27 for patients with rectal adenocarcinoma treated with adjuvant chemotherapy.

Rectal adenocarcinoma (READ) constitutes one-third of newly diagnosed colorectal cancer cases. Surgery, chemotherapy and concurrent chemoradiotherapy are the main treatments to improve patient outcomes for READ. However, patients with READ receiving these treatments eventually relapse, leading to a poor survival outcome. The present study collected surgical specimens from patients with READ and determined that cytoplasmic cell division cycle 27 (CDC27) expression was associated with the risk of lymph node metastasis and distant metastasis. Nuclear CDC27 expression was negatively associated with 5-year disease-free survival (DFS) and 5-year overall survival (OS) rates. Multivariate Cox proportional regression analysis showed that nuclear CDC27 was an independent prognostic factor in the patients with READ, especially in those treated with adjuvant chemotherapy. High nuclear CDC27 expression was significantly associated with poorer 5-year DFS (HR, 2.106; 95% CI, 1.275-3.570; P=0.003) and 5-year OS (HR, 2.369; 95% CI, 1.270-4.6810; P=0.005) rates. The data indicated that cytoplasmic CDC27 expression could affect tumor progression and that it plays an important role in metastasis. Nuclear CDC27 expression was markedly associated with poorer survival outcomes and was an independent prognostic factor in patients with postoperative adjuvant chemotherapy-treated READ. Thus, CDC27 expression serves as a potential prognostic marker for rectal tumor progression and chemotherapy treatment.

Dual inhibition of TGFß signaling and CSF1/CSF1R reprograms tumor-infiltrating macrophages and improves response to chemotherapy via suppressing PD-L1.

TGFß contributes to chemoresistance in advanced colorectal cancer (CRC) via diverse immune-microenvironment mechanisms. Here, we found that cancer cell autonomous TGFß directly triggered tumor programmed cell death 1 ligand 1 (PD-L1) upregulation, resulting in resistance to chemotherapy. Inhibition of tumor PD-L1 expression sensitized cancer cells to chemotherapy, reduced lung metastasis and increased the influx of CD8+ T cells. However, chemorefractory cancer cell-derived CSF1 recruited TAMs for TGFß-mediated PD-L1 upregulation via a vicious cycle. High infiltration of macrophages was clinically correlated with the status of tumor PD-L1 after chemotherapy treatment in CRC patients. We found that depletion of immunosuppressive CSF1R+ TAM infiltration and blockade of the TGFß receptor resulted in an increased influx of cytotoxic CD8+ T and effector memory CD8+ cells, a reduction in regulatory T cells, and a synergistic inhibition of tumor growth when combined with chemotherapy. These findings show that CSF1R+ TAMs and TGFß are the dominant components that regulate PD-L1 expression within the immunosuppressive tumor microenvironment, providing a therapeutic strategy for advanced CRC patients.

Targeted Next-generation Sequencing Reveals a Wide Morphologic and Immunophenotypic Spectrum of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma.

Primary intestinal T-cell lymphoma (PITL) is highly aggressive and includes celiac disease-related enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and primary intestinal peripheral T-cell lymphoma, not otherwise specified (ITCL-NOS). MEITL is the most common PITL in Asia, comprising of monomorphic medium-sized cells typically expressing CD8, CD56, and cytotoxic granules. Occasional cases with intermediate features between MEITL and ITCL-NOS are difficult to be classified and warrant further investigation. We collected 54 surgically resected PITLs from Taiwan, with 80% presenting with bowel perforation. The overall outcome was poor with a median survival of 7 months. Based on histopathology (monomorphic vs. pleomorphic) and immunophenotype, we classified these cases into 4 groups: MEITL with typical immunophenotype (n=34), MEITL with atypical immunophenotype (n=5), pleomorphic PITL with MEITL-like immunophenotype (n=6), and ITCL-NOS (n=9). There was no EATL in our cohort. Targeted next-generation sequencing of the first 3 groups showed highly prevalent loss-of-function mutations for SETD2 (85%, 80%, and 83%, respectively) and frequent activating mutations for STAT5B (64%, 60%, and 50%, respectively) and JAK3 (38%, 20%, and 50%, respectively). In contrast, ITCL-NOS cases had less frequent mutations of SETD2 (56%) and STAT5B (11%) and rare JAK3 mutations (11%). Our results suggest that there is a wider morphologic and immunophenotypic spectrum of MEITL as currently defined in the 2017 WHO classification. MEITL with atypical immunophenotype and PITL with MEITL-like immunophenotype shared clinicopathologic and molecular features similar to MEITL but distinct from ITCL-NOS, indicating that such cases may be considered as immunophenotypic or histopathologic variants of MEITL.

Fine Tuning Alkyl Substituents on Dithienoquinoxaline-Based Wide-Bandgap Polymer Donors for Organic Photovoltaics.

The molecular design of wide-bandgap conjugated polymer donors (WB-CPDs) is a promising strategy for tuning the bulk heterojunction blend film morphologies to achieve high-performance organic photovoltaic (OPV) devices. Herein, we synthesize two WB-CPDs, namely, PBQ-H and PBQ-M, with and without methyl groups on the fused-dithieno[3,2-f:2',3'-h]quinoxaline (DTQx) moiety. We systematically investigate their structure-property relationship and OPV performances. The AFM and 2D grazing-incidence wide-angle X-ray scattering (GIWAXS) studies reveal that the PBQ-H:BO-4Cl BHJ blend shows strengthened aggregation behavior and stronger π-π stacking on face-on orientation compared with the PBQ-M:BO-4Cl BHJ blend, enhancing the phase separation, charge transport, and fill factor (FF). Blend film absorption spectra, however, show that the PBQ-H:BO-4Cl BHJ blend exhibits a lower absorption coefficient than that of the PBQ-M:BO-4Cl BHJ blend, which decreases the short-circuit current density (JSC). As a consequence, the optimized PBQ-H:BO-4Cl BHJ blend delivers a higher power conversion efficiency (PCE) of 12.88% with a JSC of 23.97 mA/cm2, an open-circuit voltage (VOC) of 0.86 V, and an FF of 62.46%, compared with the PBQ-M:BO-4Cl BHJ blend (PCE of 11.81% with a JSC of 24.78 mA/cm2, a VOC of 0.85 V, and an FF of 56.11%). Overall, this work demonstrates that alkyl group substitution on the DTQx moiety on the basis of WB-CPDs is critical for controlling the film morphology and thus obtaining high OPV performances.

ABO blood type and clinical characteristics of patients with ulcerative colitis: A hospital-based study in central Taiwan.

BACKGROUND: The variations in ABO blood groups are reported to be associated with multiple disorders, including ulcerative colitis (UC). We aimed to investigate the distribution of ABO blood groups in UC patients and explore its impact on disease severity. METHODS: We retrospectively collected 129 UC patients diagnosed at our hospital between January 2000 and November 2019. Clinical characteristics, ABO blood groups, and operation rates were analyzed. RESULTS: The mean diagnostic age of patients was 38.97 years. Males accounted for the majority of all patients (62.8%). Of 129 patients, 43 (33.3%) were blood type O, 41 (31.8%) were blood type A, 38 (29.5%) were blood type B, and 7 (5.4%) were blood type AB. Although our patients had higher ratio of blood type A comparing our general population, there was no statistically significant association of ABO blood types distribution between these two groups (p = 0.1906). In the subgroup analysis, there were no significant difference of disease locations and operation rates between different ABO blood groups. Furthermore, blood type A patients had higher serum hemoglobin (Hb) levels compared to blood type O patients (13.31 g/dL vs. 12.30 g/dL, p = 0.0347). Blood type A patients had lower serum erythrocyte sedimentation rate (ESR) levels compared to blood type O patients (12.46 mm/hour vs. 21.5 mm/hour, p = 0.0288). Blood type O had higher serum ESR levels compared to non-O groups (p = 0.0228). In the ABO blood groups and mean diagnostic age (≤ 40 years or > 40 years), there were no statistically significant difference between these two age groups, p = 0.5515. CONCLUSIONS: Our results showed ABO blood groups are not associated with UC in spite of a higher ratio of blood type A in our patients. Blood type O patients had higher serum ESR levels; however, blood type A patients had higher Hb levels.

Green-Solvent-Processable Organic Photovoltaics with High Performances Enabled by Asymmetric Non-Fullerene Acceptors.

In this work, two asymmetric non-fullerene acceptors (NFAs), BTP-EHBO-4F and BTP-PHD-4F, are designed to be applied in green-solvent-processable organic photovoltaics (OPVs). BTP-EHBO-4F and BTP-PHD-4F show good solubilities in green solvent o-xylene. As a result, PM6:BTP-EHBO-4F-based devices exhibit outstanding photovoltaic performances using o-xylene as a solvent. By comparison, due to the poor solubility of Y6 in o-xylene, PM6:Y6-based devices show poor performances. Owing to the favorable phase separation, molecule packing, and orientation observed from atomic force microscopy (AFM) and grazing-incidence wide-angle X-ray scattering (GIWAXS) measurements, PM6:BTP-PHD-4F-based devices demonstrate a PCE of 15.91% with a VOC of 0.87 V, a JSC of 25.64 mA/cm2, and an FF of 71.34%. Moreover, PM6:BTP-EHBO-4F-based devices exhibit an impressive PCE of 16.82% with a VOC of 0.85 V, a JSC of 26.12 mA/cm2, and an FF of 75.78%, which is outstanding for OPVs using o-xylene as a solvent.

Elucidating End-Group Modifications of Carbazole-Based Nonfullerene Acceptors in Indoor Applications for Achieving a PCE of over 20.

In this work, two DTSiC-based nonfullerene acceptors (NFAs), (2,2'-((2Z,2'Z)-((12-(heptadecan-9-yl)-4,4,7,7-tetraoctyl-7,12-dihydro-4H-thieno[2',3':4,5]silolo[3,2-b]thieno[2',3':4,5]silolo[2,3-h]carbazole-2,9-diyl)bis(methaneylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile) (DTSiC-IC) and (2,2'-((5Z,5'Z)-((12-(heptadecan-9-yl)-4,4,7,7-tetraoctyl-7,12-dihydro-4H-thieno[2',3':4,5]silolo[3,2-b]thieno[2',3':4,5]silolo[2,3-h]carbazole-2,9-diyl)bis(methaneylylidene))bis(6-oxo-5,6-dihydro-4H-cyclopenta[c]thiophene-5,4-diylidene))dimalononitrile) (DTSiC-TC), are designed with various end groups (IC and TC). To explore the effect of end-group modifications, photovoltaic performance under AM 1.5G and indoor conditions are comprehensively studied. Compared with DTSiC-IC, DTSiC-TC manifests red-shifted and stronger absorption, downshifted lowest unoccupied molecular orbital (LUMO), and pronounced face-on packing characteristics. As we envisaged, the PM7:DTSiC-TC-based devices outperform the PM7:DTSiC-IC-based devices in both AM 1.5G and indoor (light-emitting diode (LED) 3000 K 1000 lux) conditions with overall higher JSC, FF, and power conversion efficiency (PCE). Furthermore, the PM7:DTSiC-TC-based devices achieve an outstanding PCE of 20.73% with a VOC of 0.87 V, a JSC of 0.095 mA/cm2, and an FF of 70.86%.

An independent predictor of poor prognosis in locally advanced rectal cancer: rs867228 in formyl peptide receptor 1 (FPR1).

Formyl peptide receptor 1 (FPR1) plays a key regulatory role in innate and adaptive immunity. Recently, we reported that the CC genotype of FPR1-E346A (rs867228, c. 1037 A > C) is an independent biomarker for patients with locally advanced rectal cancer (LARC) who received preoperative concurrent chemoradiotherapy (CCRT). Pharmacologic inhibition of FPR1 decreased the migration and infiltration of T lymphocytes into tumor microenvironment after CCRT.

Simultaneous Improvement of Efficiency and Stability of Organic Photovoltaic Cells by using a Cross-Linkable Fullerene Derivative.

Improving power conversion efficiencies (PCEs) and stability are two main tasks for organic photovoltaic (OPV) cells. In the past few years, although the PCE of the OPV cells has been considerably improved, the research on device stability is limited. Herein, a cross-linkable material, cross-linked [6,6]-phenyl-C61-butyric styryl dendron ester (c-PCBSD), is applied as an interfacial modification layer on the surface of zinc oxide and as the third component into the PBDB-TF:Y6-based OPV cells to enhance photovoltaic performance and long-term stability. The PCE of the OPV cells that underwent the two-step modification increased from 15.1 to 16.1%. In particular, such OPV cells exhibited much better stability under both thermal and air conditions because of the decreased number of interfacial defects and stable interfacial and active layer morphologies. The results demonstrated that the introduction of a cross-linkable fullerene derivative into the interfacial and active layers is a feasible method to improve the PCE and stability of OPV cells.

Immunogenic Cell Death by the Novel Topoisomerase I Inhibitor TLC388 Enhances the Therapeutic Efficacy of Radiotherapy.

Rectal cancer accounts for 30-40% of colorectal cancer (CRC) and is the most common cancer-related death worldwide. The preoperative neoadjuvant chemoradiotherapy (neoCRT) regimen is the main therapeutic strategy for patients with locally advanced rectal cancer (LARC) to control tumor growth and reduce distant metastasis. However, 30-40% of patients achieve a partial response to neoCRT and suffer from unnecessary drug toxicity side effects and a risk of distant metastasis. In our study, we found that the novel topoisomerase I inhibitor lipotecan (TLC388) can elicit immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT exposure. Lipotecan thereby increases cancer immunogenicity and triggers an antitumor immune response to attract immune cell infiltration within the tumor microenvironment (TME) in vitro and in vivo. Taken together, these results show that lipotecan can remodel the tumor microenvironment to provoke anticancer immune responses, which can provide potential clinical benefits to the therapeutic efficacy of neoCRT in LARC patients.

Polymorphism of formyl peptide receptor 1 (FPR1) reduces the therapeutic efficiency and antitumor immunity after neoadjuvant chemoradiotherapy (CCRT) treatment in locally advanced rectal cancer.

Immunosurveillance and immunoscavenging prompted by preoperative chemoradiotherapy (CCRT) may contribute to improve local control and increase survival outcomes for patients with locally advanced rectal cancer (LARC). In this study, we investigated several genotypes of pattern recognition receptors (PRRs) and their impact on therapeutic efficacy in LARC patients treated with CCRT. We found that homozygosis of formyl peptide receptor 1 (FPR1) (E346A/rs867228) was associated with reduced 5-year overall survival (OS) by Kaplan-Meier analysis (62% vs. 81%, p = 0.014) and multivariate analysis [hazard ratio (HR) = 3.383, 95% CI = 1.374-10.239, p = 0.007]. Moreover, in an animal model, we discovered that the FPR1 antagonist, Boc-MLF (Boc-1), reduced CCRT therapeutic efficacy and decreased cytotoxic T cells and T effector memory cells after chemoradiotherapy treatment. Pharmacologic inhibition of FPR1 by Boc-1 decreased T lymphocyte migration to irradiated tumor cells. Therefore, these results revealed that the FPR1 genotype participates in CCRT-elicited anticancer immunity by reducing T lymphocytes migration and infiltration, and that the FPR1-E346A CC genotype can be considered an independent biomarker for chemo- and radiotherapy outcomes.