[Efficacy and Safety of Venetoclax-Based Induction Therapy in Acute Myeloid Leukemia].

AbstractObjective: To investigate the efficacy and safety of venetoclax-based induction chemotherapy in newly diagnosed (ND) patients ineligible for intensive therapy and patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). METHODS: The clinical data of 51 newly diagnosed patients ineligible for intensive therapy and patients with R/R AML treated in the Department of Hematology of Xijing Hospital from February 1, 2021 to April 30, 2022 were retrospectively analyzed. The incidence of complete remission (CR)/CR with incomplete hematological recovery (CRi), objective remission rate (ORR), minimal residual disease (MRD) status, advense events (AE), overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: Among 51 patients, 32 patients were newly diagnosed patients unfit for intensive therapy, with a median age of 60 (29-88) years, and 19 patients were R/R patients, with a median age of 49 (22-92) years. The median cycles of VEN-based treatment in the two groups were both 2. The CR/CRi rates in the ND-AML and R/R-AML group after one course of induction treatment were 65.6% and 36.9%, respectively, and the ORR were 81.3% and 42.1%, respectively. The cumulative CR/CRi rates after 1-3 courses of VEN-based treatment were 71.9% and 47.4%, respectively. The MRD negativity rates of patients achieving CR/CRi were 69.6% and 33.3%, respectively. In the ND-AML and R/R-AML group, the median PFS were 8(5-11) and 3(1-5) months, and the median OS were 13 (6-20) and 5 (3-7) months, respectively. The median OS of patients achieving CR/CRi in both groups was significantly better than that of patients not achieving CR/CRi (13 months vs 4 months; OS not reached vs 4 months). During the first induction cycle, the incidence of grade 3 or higher granulocytopenia, anemia and thrombocytopenia was 96%, 90.2% and 84.3%, respectively. 30 patients (58.8%) had granulocytopenia with fever. The most common non-hematological AE was infection (12/51, 23.5%), followed by gastrointestinal symptoms (6/51, 11.8%). CONCLUSION: The VEN-based strategy has good treatment response and tolerance in newly diagnosed patients unfit for intensive therapy and R/R AML. The most common AEs are hematological toxicities and infection.

Orthogonal Optimization, Characterization, and In Vitro Anticancer Activity Evaluation of a Hydrogen Peroxide-Responsive and Oxygen-Reserving Nanoemulsion for Hypoxic Tumor Photodynamic Therapy.

Tumor hypoxia can seriously impede the effectiveness of photodynamic therapy (PDT). To address this issue, two approaches, termed in situ oxygen generation and oxygen delivery, were developed. The in situ oxygen generation method uses catalysts such as catalase to decompose excess H2O2 produced by tumors. It offers specificity for tumors, but its effectiveness is limited by the low H2O2 concentration often present in tumors. The oxygen delivery strategy relies on the high oxygen solubility of perfluorocarbon, etc., to transport oxygen. It is effective, but lacks tumor specificity. In an effort to integrate the merits of the two approaches, we designed a multifunctional nanoemulsion system named CCIPN and prepared it using a sonication-phase inversion composition-sonication method with orthogonal optimization. CCIPN included catalase, the methyl ester of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), photosensitizer IR780, and perfluoropolyether. Perfluoropolyether may reserve the oxygen generated by catalase within the same nanoformulation for PDT. CCIPN contained spherical droplets below 100 nm and showed reasonable cytocompatibility. It presented a stronger ability to generate cytotoxic reactive oxygen species and consequently destroy tumor cells upon light irradiation, in comparison with its counterpart without catalase or perfluoropolyether. This study contributes to the design and preparation of oxygen-supplementing PDT nanomaterials.

Chromosome 1q21 gain is an adverse prognostic factor for newly diagnosed multiple myeloma patients treated with bortezomib-based regimens.

Chromosome 1q21 aberration is one of the most common cytogenetic abnormalities in multiple myeloma, and is considered an important prognostic factor. The present study analyzed the clinical relevance and prognostic impact of 1q21 gain in 194 patients with newly diagnosed multiple myeloma treated with bortezomib-based regimens. 1q21 gain was detected in 45.9% (89/194) of patients, and those with 1q21 gain had a worse prognosis. Strikingly, our results showed that excluding the effects of other coinciding genetic anomalies, patients carrying at least four copies of 1q21 had worse survival outcome. Moreover, del(13q) strongly correlates with 1q21 gain, and the coexistence of del(13q) and 1q21 gain plays an important role in reducing PFS and OS times. Therefore, 1q21 gain should be considered a high-risk feature in multiple myeloma patients treated with a bortezomib-based regimen.

[Clinical Characteristics and Prognosis of Systemic Anaplastic Large Cell Lymphoma].

OBJECTIVE: To evaluate the clinical characteristics, treatment and prognosis of systemic anaplastic large cell lymphoma(sALCL). METHODS: The clinical data of 90 cases with sALCL treated in the Department of Hematology of the Affiliated Xijing Hospital of Air Force Medical University from November 2018 to October 2021 were retrospectively analyzed. The clinical features, treatment and prognosis were summarized and the prognostic factors were investigated. RESULTS: There were 58 males and 32 females, with a median age of 32 (12-73) years old. 69 (76.7%) patients had Ann Arbor stage Ⅲ-Ⅳ disease and half of the patients had extranodal infiltration. The median age was 27(12-72) years of the 60 ALK+ patients while 53(15-73) years of the 30 ALK- patients, and it was significantly different in the age of onset between the two group(P<0.01). 88 patients received first line chemotherapy, and 50(568%) cases achieved complete remission(CR). IPI score≥3 was an independent risk factor for CR. The median progressive free survival(PFS) and overall survival(OS) of the patients were not reached. Multivariate analysis showed that no achievement of CR after first-line therapy was a significant prognostic factor influencing PFS and OS. CONCLUSION: sALCL mainly occurs in males and most patients were in advanced stage. Half of the patients had extranodal involvement. The CR rate after first-line chemotherapy was 568%, and IPI score≥3 was a significant prognostic factor for CR. No achievement of CR after first-line therapy is poorly prognostic for PFS and OS.

Systematic analysis of prognostic significance, functional enrichment and immune implication of STK10 in acute myeloid leukemia.

BACKGROUND: Despite deeper understanding of the genetic landscape of acute myeloid leukemia (AML), the improvement of survival is still a great challenge. STK10 is overexpressed in several cancers with functions varying according to cancer types. But the functions of STK10 in AML has never been reported. METHODS: We analyzed the expression, prognosis and potential functions of STK10 utilizing public web servers. Metascape and the String database were used for functional and protein-protein interaction analyses. RESULTS: We found STK10 was enriched in blood & immune cells and overexpressed in AML. High STK10 expression was associated with poor overall survival, which was also identified in the subgroups of patients ≤ 60 years old and patients with non-high-risk cytogenetics. We demonstrated genes associated with STK10 were enriched in blood, spleen and bone marrow, influencing the immune function and biological process of AML. ITGB2 and ITGAM might directly interact with STK10 and were associated with poor prognosis. Besides, STK10 was associated with the infiltration of immune cells and immune checkpoints, like HLA-E, CD274 and GAL-9. CONCLUSIONS: The present study was the original description of STK10 in AML and set the stage for developing STK10 as a new prognostic marker or therapeutic target for AML.

The PARP1 Inhibitor Niraparib Represses DNA Damage Repair and Synergizes with Temozolomide for Antimyeloma Effects.

Purpose: Poly(ADP-ribose) polymerase 1 (PARP1) is necessary for single-strand break (SSB) repair by sensing DNA breaks and facilitating DNA repair through poly ADP-ribosylation of several DNA-binding and repair proteins. Inhibition of PARP1 results in collapsed DNA replication fork and double-strand breaks (DSBs). Accumulation of DSBs goes beyond the capacity of DNA repair response, ultimately resulting in cell death. This work is aimed at assessing the synergistic effects of the DNA-damaging agent temozolomide (TMZ) and the PARP inhibitor niraparib (Nira) in human multiple myeloma (MM) cells. Materials and Methods: MM RPMI8226 and NCI-H929 cells were administered TMZ and/or Nira for 48 hours. CCK-8 was utilized for cell viability assessment. Cell proliferation and apoptosis were detected flow-cytometrically. Immunofluorescence was performed for detecting γH2A.X expression. Soft-agar colony formation assay was applied to evaluate the antiproliferative effect. The amounts of related proteins were obtained by immunoblot. The combination index was calculated with the CompuSyn software. A human plasmacytoma xenograft model was established to assess the anti-MM effects in vivo. The anti-MM activities of TMZ and/or Nira were evaluated by H&E staining, IHC, and the TUNEL assay. Results: The results demonstrated that cotreatment with TMZ and Nira promoted DNA damage, cell cycle arrest, and apoptotic death in cultured cells but also reduced MM xenograft growth in nude mice, yielding highly synergistic effects. Immunoblot revealed that TMZ and Nira cotreatment markedly increased the expression of p-ATM, p-CHK2, RAD51, and γH2A.X, indicating the suppression of DNA damage response (DDR) and elevated DSB accumulation. Conclusion: Inhibition of PARP1 sensitizes genotoxic agents and represents an important therapeutic approach for MM. These findings provide preliminary evidence for combining PARP1 inhibitors with TMZ for MM treatment.

PELO facilitates PLK1-induced the ubiquitination and degradation of Smad4 and promotes the progression of prostate cancer.

PLK1 and Smad4 are two important factors in prostate cancer initiation and progression. They have been reported to play the opposite role in Pten-deleted mice, one is an oncogene, the other is a tumor suppressor. Moreover, they could reversely regulate the PI3K/AKT/mTOR pathway and the activation of MYC. However, the connections between PLK1 and Smad4 have never been studied. Here, we showed that PLK1 could interact with Smad4 and promote the ubiquitination and degradation of Smad4 in PCa cells. PLK1 and PELO could bind to different domains of Smad4 and formed a protein complex. PELO facilitated the degradation of Smad4 through cooperating with PLK1, thereby resulting in proliferation and metastasis of prostate cancer cell. Changes in protein levels of Smad4 led to the alteration of biological function that caused by PLK1 in prostate cancer cells. Further studies showed that PELO upregulation was positively associated with high grade PCa and knockdown of PELO expression significantly decreased PCa cell proliferation and metastasis in vitro and vivo. PELO knockdown in PCa cells could enhance the tumor suppressive role of PLK1 inhibitor. In addition, blocking the interaction between PELO and Smad4 by using specific peptide could effectively inhibit PCa cell metastasis ability in vitro and vivo. Overall, these findings identified a novel regulatory relationship among PLK1, Smad4 and PELO, and provided a potential therapeutic strategy for advanced PCa therapy by co-targeting PLK1 and PELO.

Development and Validation of a Novel Prognostic Model for Overall Survival in Newly Diagnosed Multiple Myeloma Integrating Tumor Burden and Comorbidities.

Background: Multiple myeloma (MM) is a highly heterogeneous disease with enormously variable outcomes. It remains to be a major challenge to conduct a more precise estimation of the survival of MM patients. The existing stratifications attached less importance to the prognostic significance of comorbidities. In the present study, we aimed to develop and validate a novel and simple prognostic stratification integrating tumor burden and comorbidities measured by HCT-CI. Method: We retrospectively enrolled 385 consecutive newly diagnosed multiple myeloma (NDMM) patients in Xijing Hospital from January 2013 to December 2020. The cohort between January 2016 and December 2020 was selected as development cohort (N = 233), and the cohort between January 2013 and December 2015 was determined as validation cohort (N = 152). By using LASSO analysis and univariate and multivariable Cox regression analyses, we developed the MM-BHAP model in the way of nomogram composed of ß2-MG, HCT-CI, ALB, and PBPC. We internally and externally validated the MM-BHAP model and compared it with ISS stage and R-ISS stage. Results: The MM-BHAP model was superior to the ISS stage and partially better than the R-ISS stage according to time-dependent AUC, time-dependent C-index, DCA, IDI, and continuous NRI analyses. In predicting OS, only the MM-BHAP stratification clearly divided patients into three groups while both the ISS stage and R-ISS stage had poor classifications in patients with stage I and stage II. Moreover, the MM-BHAP stratification and the R-ISS stage performed well in predicting PFS, but not for the ISS stage. Besides, the MM-BHAP model was also applied to the patients with age ≤65 or age >65 and with or without HRCA and could enhance R-ISS or ISS classifications. Conclusions: Our study offered a novel simple MM-BHAP stratification containing tumor burden and comorbidities to predict outcomes in the real-world unselected NDMM population.

Long-Lived Room Temperature Phosphorescence Crystals with Green Light Excitation.

Long-lived room temperature phosphorescence (RTP) materials are promising for applications in various fields including security information, medical diagnostics, and molecular imaging because of their unique optical properties. Previous RTP materials are mainly excited by ultraviolet light, while synthesizing long-lived RTP materials with visible-light-excitation remains a challenge. In particular, long-lived RTP materials that can be excited by green light are rare. Herein, a feasible and concise chemical strategy for constructing hydrogen-bonded frameworks in an aqueous environment is developed to fabricate large-size, green-light-excited, and excitation-dependent long-lived RTP carbon dot crystals (m,p/CDs-ME). The RTP performance of the crystals exhibits strong excitation wavelength dependence, leading to a full range of visible-light tuning from blue to red. Importantly, the maximum excitation wavelength of the RTP crystals is around 500 nm, thus successfully realizing green light excitation. m,p/CDs-ME presents long-lived phosphorescence (130 ms) under 500 nm excitation in aqueous solution, making it highly suitable for dopamine detection. This work not only provides a general guideline for the development of large size long-lived RTP crystals but also extends the operation scope of long-lived RTP materials in the detection of biomarkers by visible light excitation.

Ultraviolet irradiation-responsive dynamic ultralong organic phosphorescence in polymeric systems.

Room temperature phosphorescence (RTP) has drawn extensive attention in recent years. Efficient stimulus-responsive phosphorescent organic materials are attractive, but are extremely rare because of unclear design principles and intrinsically spin-forbidden intersystem crossing. Herein, we present a feasible and facile strategy to achieve ultraviolet irradiation-responsive ultralong RTP (IRRTP) of some simple organic phosphors by doping into amorphous poly(vinyl alcohol) matrix. In addition to the observed green and yellow afterglow emission with distinct irradiation-enhanced phosphorescence, the phosphorescence lifetime can be tuned by varying the irradiation period of 254 nm light. Significantly, the dynamic phosphorescence lifetime could be increased 14.3 folds from 58.03 ms to 828.81 ms in one of the obtained hybrid films after irradiation for 45 min under ambient conditions. As such, the application in polychromatic screen printing and multilevel information encryption is demonstrated. The extraordinary IRRTP in the amorphous state endows these systems with a highly promising potential for smart flexible luminescent materials and sensors with dynamically controlled phosphorescence.

Simple Vanilla Derivatives for Long-Lived Room-Temperature Polymer Phosphorescence as Invisible Security Inks.

Developing novel long-lived room-temperature polymer phosphorescence (RTPP) materials could significantly expand their application scope. Herein, a series of RTPP materials based on eight simple vanilla derivatives for security ink application are reported. Attributed to strong mutual hydrogen bonding with polyvinyl alcohol (PVA) matrix, vanilla-doped PVA films exhibit ultralong phosphorescence emission under ambient conditions observed by naked eyes, where methyl vanillate shows the longest emission time up to 7 s. Impressively, when vanilla-doped PVA materials are utilized as invisible security inks, and the inks not only present excellent luminescent emission stability under ambient conditions but also maintain perfect reversibility between room temperature and 65°C for multiple cycles. Owing to the unique RTPP performance, an advanced anticounterfeiting data encoding/reading strategy based on handwriting technology and complex pattern steganography is developed.

Treatment options for older unfit patients with acute myeloid leukemia.

Older acute myeloid leukemia patients usually experience a bleak outcome, especially those in the unfit group. For this unfit category, intensive chemotherapy and allogeneic stem cell transplantation are usually accompanied by higher early mortality, which results from higher risk genetic profiles and worse psychological and physiological conditions. The significant improvement in genetic technology recently has driven the appearance of several mutation-targeted therapies, such as FLT3, Bcl-2, IDH and Hedgehog pathway inhibitors and an anti-CD33 antibody-drug conjugate, which have changed enormously the therapeutic landscape of acute myeloid leukemia. This review describes the treatment dilemma of the unfit group and discusses the objective clinical data of each targeted drug and mechanisms of resistance, with a focus on combination strategies with fewer toxicities and abrogation of drug resistance.

Ectopic expression of an AGAMOUS homologue gene in Jatropha curcas causes early flowering and heterostylous phenotypes.

Jatropha curcasseeds are abundant in biodiesel, and low seed yields are linked to poor quality female flowers, which creates a bottleneck for Jatropha seed utilization. Therefore, identifying the genes associated with flowering is crucial for the genetic enrichment of seed yields. Here, we identified an AGAMOUS homologue gene (JcAG) from J. curcas. We found that reproductive organs had higher JcAG expression than vegetative organs, particularly the carpel. Rosette leaves were small and misshapen in 35S:JcAG transgenic lines in comparison with those in wild-type plants. JcAG overexpression caused an extremely early flowering, delayed perianth and stamen filament development, small flowers, and significantly shorter Arabidopsis plants with little fruit. In the JcAG-overexpressing line, the homeotic transformation of sepals into pistillate organs was observed, and floral meristem and organ identity genes were regulated. This study provides insights into the JcAG's function and benefits to our knowledge of the underlying the genetic mechanisms related to floral sex differentiation in Jatropha.

Comparison of Survival Between Autologous and Allogeneic Stem Cell Transplantation in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: A Meta-Analysis.

This study aimed to compare the efficacy of allogeneic stem cell transplantation (allo-SCT) versus autologous SCT (auto-SCT) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). Medline, CENTRAL, and EMBASE databases through December 31, 2019 were searched. The primary endpoints were overall survival (OS) and progression-free survival (PFS) rates. The secondary outcomes include transplant-related mortality (TRM), event-free survival, relapse/or progression, and nonrelapse mortality (NRM). The 18 retrospective studies enrolled 8,058 B-NHL patients (allo-SCT = 1,204; auto-SCT = 6,854). The OS was significantly higher in patients receiving auto-SCT than allo-SCT (pooled odds ratio [OR]: 1.69, 95% confidence interval [CI]: 1.29 to 2.22, P < 0.001), but no significant difference was found in PFS (pooled OR: 0.98, 95% CI: 0.69 to 1.38, P = 0.891). Auto-SCT patients also had lower TRM and NRM (TRM: OR = 0.23, P < 0.001; NRM: OR = 0.16, P < 0.001), but higher relapse or progression rate (OR = 2.37, P < 0.001) than allo-SCT patients. Subgroup analysis performed for different grades and subtypes of B-NHL showed higher OS in auto-SCT patients with high-grade B-NHL and diffused large B-cell lymphoma (DLBCL). There was, nevertheless, higher PFS in allo-SCT patients with low-grade B-NHL and follicular lymphoma (FL), and lower PFS in allo-SCT patients with DLBCL than their auto-SCT counterparts. In conclusion, the meta-analysis demonstrated that relapsed or refractory B-NHL patients who received auto-SCT have improved OS than those treated with allo-SCT, especially among those with DLBCL, but lower PFS among those with FL. However, the study is limited by a lack of randomized trials, patients' heterogeneity, and possible selection bias.

Accuracy improvement of quantitative LIBS analysis of coal properties using a hybrid model based on a wavelet threshold de-noising and feature selection method.

A hybrid model based on a wavelet threshold de-noising (WTD) and recursive feature elimination with cross-validation (RFECV) method was proposed to improve the measurements in quantitative analysis of coal properties using laser-induced breakdown spectroscopy (LIBS). First, a modified threshold of WTD was proposed based on wavelet coefficient theory. Interference of noise in the LIBS spectrum was reduced by using this modified method. Then, the RFECV method was applied to extract effective features from the de-noised LIBS spectrum. Finally, support vector regression (SVR) models of coal properties were established by the selected features. A validation set was used to verify the effectiveness and robustness of the hybrid model. The improvement of the hybrid model on the quantitative analysis of each index of coal properties (heat value, ash, volatile content) was studied and discussed. By using the proposed model, the determination coefficient (R2), root mean square error of prediction, average relative error, and relative standard deviation were all significantly improved over the original spectra model. The results demonstrated that the proposed model could effectively improve the accuracy and precision of LIBS quantitative analysis for coal properties.

SERS-fluorescence-superresolution triple-mode nanoprobe based on surface enhanced Raman scattering and surface enhanced fluorescence.

Multifunctional nanoprobes play important roles in cell imaging and sensing. Here, we present a novel optical nanoprobe based on surface enhanced Raman scattering (SERS) and surface enhanced fluorescence (SEF), which can realize the SERS-fluorescence and superresolution triple-mode imaging of cancer cells. Compared with other previously reported multifunctional nanoprobes, the proposed nanoprobe holds two exquisite properties. The first one is that, in addition to normal SERS and fluorescence imaging, the nanoprobe can also be used for single molecule localization microscopy (SMLM) imaging, which helps compensate for the diffraction limited spatial resolution of normal SERS and fluorescence imaging. The second one is that, other than simple fluorescence, SEF is used in the nanoprobe to produce a stronger signal for fluorescence imaging and, more importantly, better photo-switching for SMLM imaging. In the experiment, we optimized the structure of the nanoprobe to obtain the best SEF effect. With the optimal structure, the triple-mode imaging of a breast cancer cell line (SKBR3) is realized. Since such triple-mode imaging of cancer cells has never been achieved before, we believe that the presented nanoprobe holds great potential for cancer cell targeting or the investigation of cell-nanomaterial interactions.

BRD4 inhibitor nitroxoline enhances the sensitivity of multiple myeloma cells to bortezomib in vitro and in vivo by promoting mitochondrial pathway-mediated cell apoptosis.

BACKGROUND: Multiple myeloma (MM) is the second most common hematological neoplasm. Wide administration of bortezomib significantly improves the survival of MM patients compared with conventional chemotherapy. Bromodomain-containing protein 4 (BRD4) inhibitors also have been demonstrated to retard cell proliferation and induce cellular apoptosis in various cancers. However, it is unclear whether the BRD4 inhibitor nitroxoline plus bortezomib has a synergistic anti-tumor effect on MM. METHODS: Cell viability was determined via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and cell apoptosis were assessed via flow cytometry. Protein expression levels were determined via western blotting. The expression of apoptosis-related proteins in xenograft tissue were detected by means of immunohistochemistry. RESULTS: Treatment with nitroxoline or bortezomib suppressed cell proliferation, and caused G0/G1 phase arrest and apoptosis in H929 and RPMI8226 cells. Furthermore, nitroxoline intensified the retardation of cell proliferation, as well as further enhanced the G0/G1 phase arrest and apoptosis induced by bortezomib in H929 and RPMI8226 cells. The western blot analysis revealed that nitroxoline or bortezomib treatment markedly diminished the levels of Bcl-2 and cyclin D1, and increased the levels of p21, Bax, cleaved PARP and cleaved caspase-3. Combination of these two agents was observed to result in further marked changes on these levels compared with nitroxoline or bortezomib treatment alone. What is more, in the xenograft tumor model, combinative treatment markedly inhibited tumor growth compared with the single drug treatment. CONCLUSION: Combination of bortezomib with nitroxoline has a synergistic anti-tumor activity in MM cells and may be a novel treatment method for MM.

Hydrophobic Plasmonic Nanoacorn Array for a Label-Free and Uniform SERS-Based Biomolecular Assay.

A surface-enhanced Raman scattering (SERS) aptasensor based on a hydrophobic assembled nanoacorn (HANA) was developed with improved reproducibility and reduced nonspecific binding effect. In the fabrication process, a hexagonal-packed gold film over nanosphere (AuFON) arrays was first obtained and used as a hydrophobic plasmonic substrate. Then, a uniform sub-3 nm molecular spacer array (containing Raman reporters) was prepared by patterning nanometric hydrophilic ultrathin patches onto the hydrophobic AuFON, in which the hydrophilic thin layer is composed of polymers and aptamers. During the sensing process, the HANA aptasensor smartly impedes the adsorption of SERS probes as Au@Ag nanocubes (Au@Ag NCs) in the absence of targets. In the presence of targets, the displacement of aptamers occurs due to the specific interaction between the targets and the aptamers, and the Au@Ag NCs can be assembled onto the hydrophilic patches on AuFON through electrostatic interactions with polymers. Thus, SERS signals of reporter molecules inside the spacer can be dramatically enhanced due to the formation of a nanoparticle-on-mirror (NPoM) array. In such a SERS aptasensor, the well-ordered distribution of SERS probes ensures excellent repeatability, while the precise subnanometer junctions guarantee high sensitivity. More importantly, since the hydrophobic surface can greatly reduce nonspecific adsorption, the tedious process of nonspecific blocking that is employed in traditional biosensors is no longer needed. Using such a SERS HANA platform, human epidermal growth factor receptor 2 (HER2) and three exosomal proteins were analyzed with high sensitivity and good reproducibility (RSD < 7%) in whole-blood samples.

Chidamide epigenetically represses autophagy and exerts cooperative antimyeloma activity with bortezomib.

Autophagy and ubiquitin proteasome system are two distinct and cooperative proteolytic pathways. The dual-pathway suppression represents a promising therapeutic strategy for multiple myeloma. Chidamide is a novel benzamide inhibitor of histone deacetylase, and shows potent antimyeloma activity. Here, we revealed the autophagy-suppressive role of chidamide in myeloma cells. We then demonstrated that chidamide treatment markedly downregulated histone deacetylase SIRT1, and simultaneously resulted in dose-dependent upregulation of acetyltransferase hMOF and histone methyltransferase EZH2, which contributed to an increase in global levels of histone H4 lysine 16 acetylation (H4k16ac) and histone H3 lysine 27 trimethylation (H3k27me3). We next confirmed concomitant upregulation of H4k16ac and H3k27me3 in the same promoter regions of the autophagy-related gene LC3B, reinforcing the specific roles for H4k16ac and H3k27me3 in mediating chidamide-induced transcriptional repression of LC3B. Finally, we provided experimental evidence that co-treatment with chidamide and proteasome inhibitor bortezomib induced clear synergistic cytotoxicity against MM cells, which was associated with increased accumulation of ubiquitinated proteins and excessive endoplasmic reticulum stress or dysregulated unfolded protein response. Our results altogether suggest that chidamide cooperatively potentiates antimyeloma activity of bortezomib, at least in part, by epigenetically repressing autophagic degradation of ubiquitinated proteins.