Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

Co-Occurrence Patterns of Soil Fungal and Bacterial Communities in Subtropical Forest-Transforming Areas.

Soil microbial communities are engineers of important biogeochemical processes and play a critical role in regulating the functions and stability of forest ecosystem. However, few studies have assessed microbial interactions during forest conversion, which is essential to the understanding of the structure and function of soil microbiome. Herein, we investigated the co-occurrence network pattern and putative functions of fungal and bacterial communities in forest-transforming areas (five sites that cover the typical forests) using high-throughput sequencing of the ITS genes and 16S rRNA. Our study showed that the bacterial network had higher average connectivity and more links than fungal network, which might indicate that the bacterial community had more complex internal interactions compared with fungal one. Alphaproteobacteria_unclassfied, Telmatobacter, 0319-6A21 and Latescibacteria_unclassfied were the keystone taxa in bacterial network. For the fungal community network, the keystone taxon was Ceratobasidium. A structural equation model indicated that the available potassium and total organic carbon were important soil environmental factors, which affected all microbial modules, including bacterial and fungi. Total nitrogen had significant effects on the bacterial module that contains a relatively rich group of nitrogen cycling functions, and pH influenced the bacterial module which have higher potential functions of carbon cycling. And, more fungal modules were directly affected by forest structure (S Tree) compared with bacterial ones. This study provides new insights into our understanding of the feedback of underground creatures to forest conversion and highlights the importance of microbial modules in the nutrient cycling process.

Characteristics of preterm births during COVID-19 mitigation measures.

BACKGROUND: During the COVID-19 pandemic, mitigation measures were associated with a reduction in preterm birth rates; while not clearly proven, this observation has sparked significant interest. AIM: To understand the cause of this reduction by exploring the characteristics of preterm birth cohorts. MATERIAL AND METHODS: We performed a retrospective cohort study where we compared women who delivered preterm in three Melbourne maternity hospitals and conceived between November 2019 and February 2020 (mitigation measures-exposed cohort) to women who delivered preterm and conceived between November 2018 and February 2019 (non-exposed cohort). We compared maternal characteristics, pregnancy complications, antenatal interventions, intrapartum care, and indications for delivery. RESULTS: In the exposed cohort, 252/3129 women delivered preterm (8.1%), vs 298/3154 (9.4%) in the non-exposed cohort (odds ratio (OR) 0.84, 95% CI 0.70-1.00, P = 0.051). The baseline characteristic of two cohorts were comparable. Rates of spontaneous preterm labour (sPTL) without preterm pre-labour rupture of membranes (PPROM) were lower in the exposed cohort (13.1% vs 24.2%, OR 0.47, P = 0.001) while PPROM occurred more often (48.0% vs 35.6%, OR 1.67, P = 0.003). With a non-statistically significant prolongation of pregnancy in the cohort exposed to mitigation measures for both sPTL without PPROM (35.4 vs 34.9 weeks, P = 0.703) and PPROM (35.6 vs 34.9 weeks, P = 0.184). The rate of spontaneous labour after PPROM was higher in the exposed cohort compared to the non-exposed cohort (40.1% vs 24.1%, OR 2.09, P < 0.001). CONCLUSION: The reduction in preterm delivery during mitigation measures may have been driven by a reduction in spontaneous labour without PPROM, which seemed to result in more PPROM later in pregnancy.

Bendamustine in the treatment of patients with indolent non-Hodgkin lymphoma refractory or relapse to rituximab treatment: An open-label, single-agent, multicenter study in China.

BACKGROUND: The optimal treatment strategy for refractory or relapse (R/R) indolent non-Hodgkin lymphoma (iNHL) has not been fully identified. This study aims to investigate the efficacy and tolerance of bendamustine hydrochloride developed in native Chinese corporation in the treatment of patients with R/R iNHL. METHODS: A total of 101 patients from 19 centers were enrolled in this study from July 2016 to February 2019. Bendamustine hydrochloride (120 mg/m2 ) was given on days 1 and 2 of each 21-day treatment cycle for six planned cycles or up to eight cycles if tolerated. Parameters of efficacy and safety were analyzed. RESULTS: The median age of the patients was 53.44 (range, 24.4-74.6) years old. A total of 56 (55.44%) patients completed at least six treatment cycles, and the relative dose intensity was 93.78%. The overall response rate was 72.28%, and the median duration of response was 15.84 months (95% confidence interval [CI], 13.77-27.48 months). Median progression-free survival was 16.52 months (95% CI, 14.72-23.41 months), and the median overall survival was not reached. Grade 3 or 4 hematologic toxicities included neutropenia (77.22%), thrombocytopenia (29.70%), and anemia (15.84%). The most frequent nonhematologic adverse events (any grade) included nausea, vomiting, fatigue, fever, decreased appetite, and weight loss. Seven patients died during the trial, and four cases may be related to the investigational drug. CONCLUSIONS: This study reveals that bendamustine hydrochloride is a feasible treatment option for the indolent B-cell non-Hodgkin lymphoma patient who has not remitted or relapsed after treatment with rituximab. All adverse events were predictable and manageable.

Foldback-crRNA-Enhanced CRISPR/Cas13a System (FCECas13a) Enables Direct Detection of Ultrashort sncRNA.

The CRISPR/Cas13a system has promising applications in clinical small noncoding RNA (sncRNA) detection because it is free from the interference of genomic DNA. However, detecting ultrashort sncRNAs (less than 20 nucleotides) has been challenging because the Cas13a nuclease requires longer crRNA-target RNA hybrids to be activated. Here, we report the development of a foldback-crRNA-enhanced CRISPR/Cas13a (FCECas13a) system that overcomes the limitations of the current CRISPR/Cas13a system in detecting ultrashort sncRNAs. The FCECas13a system employs a 3'-terminal foldback crRNA that hybridizes with the target ultrashort sncRNA, forming a double strand that "tricks" the Cas13a nuclease into activating the HEPN structural domain and generating trans-cleavage activity. The FCECas13a system can accurately detect miRNA720 (a sncRNA currently known as tRNA-derived small RNA), which is only 17 nucleotides long and has a concentration as low as 15 fM within 20 min. This FCECas13a system opens new avenues for ultrashort sncRNA detection with significant implications for basic biological research, disease prognosis, and molecular diagnosis.

Species richness disparity in tropical terrestrial herbaceous floras: Evolutionary insight from Collabieae (Orchidaceae).

Species richness is spatially heterogeneous even in the hyperdiverse tropical floras. The main cause of uneven species richness among the four tropical regions are hot debated. To date, higher net diversification rates and/or longer colonization time have been usually proposed to contribute to this pattern. However, there are few studies to clarify the species richness patterns in tropical terrestrial floras. The terrestrial tribe Collabieae (Orchidaceae) unevenly distributes in the tropical regions with a diverse and endemic center in Asia. Twenty-one genera 127 species of Collabieae and 26 DNA regions were used to reconstruct the phylogeny and infer the biogeographical processes. We compared the topologies, diversification rates and niche evolutionary rates of Collabieae and regional lineages on empirical samplings and different simulated samplings fractions respectively. Our results suggested that the Collabieae originated in Asia at the earliest Oligocene, and then independently spread to Africa, Central America, and Oceania since the Miocene via long-distance dispersal. These results based on empirical data and simulated data were similar. BAMM, GeoSSE and niche analyses inferred that the Asian lineages had higher net diversification and niche evolutionary rates than those of Oceanian and African lineages on the empirical and simulated analyses. Precipitation is the most important factor for Collabieae, and the Asian lineage has experienced more stable and humid climate, which may promote the higher net diversification rate. Besides, the longer colonization time may also be associated with the Asian lineages' diversity. These findings provided a better understanding of the regional diversity heterogeneity in tropical terrestrial herbaceous floras.

Association of caspase-1 gene polymorphisms with rheumatoid arthritis risk in a Chinese Han population.

The goals of present research are to investigate if the genetic polymorphisms in the caspase-1 (CASP1) gene are associated with the risk of rheumatoid arthritis (RA) and the clinical characteristics of the illness in Han patients from China. Our team studied the CASP1 rs2409062 A/G polymorphisms in 1095 healthy controls and 805 RA patients, while the genotype was identified via a custom-by-design 48-Plex single nucleotide polymorphism (SNP) scan™ Kit. The mRNA expression levels of the CASP1 in 40 RA cases and 40 healthy controls were detected by qRT-PCR, while blood plasma levels of the CASP1 in 40 RA cases and 40 paired controls measured via ELISA. Our research showed that the CASP1 rs2409062 A/G polymorphisms were related to an elevated risk for RA. By stratified analysis, our team discovered a remarkably elevated RA risk in females sufferers, age ≥ 55, CRP-positive, or DAS28 < 3.20. In contrast to the control group, the mean level of CASP1 protein in the plasma of RA cases rised significantly. Moreover, RA cases displayed significantly greater levels of CASP1 mRNA versus the control group (P < 0.05). Those outcomes reveal that the CASP1 rs2409062 A/G gene polymorphisms are associated with an elevated risk for RA in a Chinese Han population.

The transvaginal mesh class action: a tertiary teaching hospital experience of all mid-urethral sling procedures performed between 1999 and 2017.

INTRODUCTION AND HYPOTHESIS: Class action against Ethicon (J&J), manufacturer of transvaginal mesh devices, including mid-urethral slings (MUS), was brought to the Federal Court of Australia in 2016 by Shine Lawyers. As a result, subpoenas to all hospitals and networks were received, which overrode patient privacy concerns. This medical record search allowed a complete audit and communication with patients to offer clinical review. This enabled a review of complications, readmission and re-operation for women who underwent a MUS for stress urinary incontinence. METHODS: A cohort study of women who underwent MUS treatment for stress urinary incontinence (SUI) at a single tertiary teaching hospital between 1999 and 2017 was carried out. The main outcome measures were the rate of readmission and re-operation following MUS procedures. These include voiding dysfunction managed by sling loosening or sling division, mesh pain or exposure managed by mesh removal and reoperation for recurrent stress urinary incontinence. RESULTS: Between 1999 and 2017, a total of 1,462 women were identified as having a MUS; of these, 1,195 (81.7%) had full patient records available. Voiding dysfunction requiring surgical intervention with sling loosening or division was 3%, excision for mesh exposure was 2%, and partial or complete excision for pain was 1% at a median of 10 years from index surgery. The reoperation rate for recurrent stress urinary incontinence was 3%. CONCLUSION(S): This audit of all MUS procedures performed at a tertiary centre confirms an overall low rate of readmission for complications and recurrent SUI surgery; this justifies its continued availability with appropriate informed consent.

Concerns about Data Integrity of 22 Randomized Controlled Trials in Women's Health.

OBJECTIVE: During a review on postpartum hemorrhage, we identified randomized controlled trials (RCTs) of one author conducted at the same time and place for the same condition, with large differences in baseline characteristics. We assessed the data integrity of the RCTs of this author. STUDY DESIGN: We undertook a focused analysis of the data integrity of all RCTs published by Dr. Ahmed M. Maged. We examined the studies for clinical logic and made pairwise comparisons of baseline characteristics and outcomes between trials. We used mathematical methods to assess whether the distribution of baseline characteristics was compatible with chance. RESULTS: Between March 2015 and December 2019, Dr. Maged published 22 RCTs (n = 3,722). The median number of participants randomized per center per month was 32 (range = 1-89). Fifteen studies were either not or retrospectively registered, with one study registered 1 year after publication. One study was submitted for publication prior to the completion of the described study period. There were many unusual findings in the studies, including biologically implausible occurrences such as the absence of an association between gestational age and birthweight in seven studies and very different body mass index between three trials, which ran at the same time in the same hospital on the same topic as well as unlikely occurrences such as limited participant drop outs. One paper contained considerable text duplication and identical data to that in a paper published by a different author group from a different hospital, with both papers submitted at the same time. Mathematical analysis of the baseline characteristics of all 22 trials indicated that at least some of the reported baseline characteristics were unlikely to be the result of proper randomization. CONCLUSION: Our analyses of the 22 RCTs of Dr. Maged suggest potential data integrity issues in at least some of them. We suggest that journals investigate according to the Committee on Publication Ethics guidelines. The procedures demonstrated in this paper may help to assess data integrity in future attempts to verify the authenticity of published RCTs. KEY POINTS: · We identified a number of findings biologically implausible in RCTs by Maged.. · Monte Carlo simulation found pooled data of Maged RCTs were unlikely result of proper randomization.. · Textual overlap and almost identical data were found between a Maged paper and another paper.. · The methods we described may be useful for future efforts in validating scientific data integrity..

Photoactivatable CRISPR/Cas12a Strategy for One-Pot DETECTR Molecular Diagnosis.

As a golden partner of recombinase polymerase amplification (RPA), CRISPR/Cas12a has been proven to solve the false-positive problem caused by nonspecific amplification perfectly; meanwhile, its trans-cleave activity has further enhanced the sensitivity. However, the solution transfer operation after tube cap opening greatly increases the risk of aerosol contamination of amplicon, which is inconsistent with point-of-care (POC) diagnostics requirements. This study proposes a photoactivated CRISPR/Cas12a strategy to achieve one-pot high-sensitivity nucleic acid detection. Using photocleavable complementary ssDNA to block crRNA, RPA amplification can smoothly pass through the exponential interval without being affected by activated Cas12a in the critical early stage. After enough amplicons were produced, the Cas12a test was activated by short bursts of ultraviolet radiation at 365 nm. This one-pot method achieved a sensitivity of 2.5 copies within 40 min. This simple and sensitive one-pot method can effectively avoid amplicon contamination and lower the threshold for molecular diagnostics in POC.

High-Selectivity Single-Nucleotide Variant Capture Technology Based on the DNA Reaction Network.

The extremely low abundance of circulating tumor DNA in blood samples has limited the development of liquid biopsy techniques for the early diagnosis of major diseases. In this study, we demonstrate a DRN-based screening technique, SCREEN, which achieves the specific capture and enrichment of low abundance SNV nucleic acid samples without selective amplification. The SCREEN technique achieved a 108-fold increase in the abundance of single-nucleotide variant (SNV) nucleic acids from highly homologous mixtures (from 0.01% to 1.08%) and has been shown to significantly increase the abundance of SNV nucleic acids from 0.1% to 51% further through two rounds of capture. As a highly effective pre-enrichment technique, SCREEN has demonstrated the ability to enhance NGS in detecting an ultralow abundance SNV nucleic acid powerfully and has high compatibility with existing molecular diagnostic methods.

Four cycles of R-CHOP followed by two applications of rituximab based on negative interim PET/CT: an analysis of a prospective trial.

BACKGROUND: R-CHOP with or without radiotherapy is the standard treatment for limited-stage diffuse large B-cell lymphoma (DLBCL). To prevent overtreatment, we assessed whether four cycles of CHOP plus six applications of rituximab was adequate with negative interim PET/CT and the role of consolidation radiotherapy specifically for patients with Waldeyer's ring DLBCL. One hundred and twenty-nine patients with limited-stage DLBCL were enrolled in this open-label, nonrandomized, single-arm, phase 2 clinical trial (NCT01804127). METHODS: All patients were initially treated with 4 cycles of R-CHOP and underwent interim PET/CT. Patients with negative PET/CT (Deauville scores 1-2) received 2 additional cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, extranodal primary or bulky disease). Otherwise, patients received another 2 cycles of R-CHOP. Patients with partial response on interim PET/CT received another 4 cycles of R-CHOP. No radiotherapy was conducted in Waldeyer's ring DLBCL patients with negative PET/CT. The primary endpoint was 3-year progression-free survival (PFS). Overall survival (OS) in this study was compared with those from a historical study (NCT 00854568159). RESULTS: One hundred fifteen interim PET/CT scans (89.1%) were negative after 4 cycles of R-CHOP. An elevated lactate dehydrogenase level was significantly associated with positive interim PET/CT (P < 0.05). A trend of inferior outcome was observed in patients with positive interim PET/CT in terms of 3-year PFS (78.6% vs. 91.9%, P = 0.24) and 3-year OS (85.7% vs. 95.6%, P = 0.16). There were no PFS or OS differences found between patients treated with 4R-CHOP+2R and those treated with 6R-CHOP from a historical control study. Patients with Waldeyer's ring DLBCL and negative interim PET/CT achieved a 3-year PFS of 87.2% and a 3-year OS of 89.7%. CONCLUSIONS: Our results suggested that for interim PET/CT-negative patients without risk factors, the extra 2 cycles of CHOP might be omitted, and radiotherapy might also be omitted in patients with Waldeyer's ring DLBCL without compromising the efficacy. These results need to be confirmed in a randomized study. TRIAL REGISTRATION: clinicaltrials.gov , NCT01804127 . Date of first registration: 05/03/2013.

Protective effect of SIRT6 on cholesterol crystal-induced endothelial dysfunction via regulating ACE2 expression.

Sirtuins are a family of highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. Among the sirtuins, SIRT1 and SIRT6 participate in the regulation of endothelial functions and play significant roles in the physiological and pathological processes of cardiovascular diseases (CVD). Recently, our study found that minute cholesterol crystals (CC) can be endocytosed by endothelial cells and further impair endothelial functions. Since previous studies have reported that angiotensin-converting enzyme (ACE2) involves Angiotensin (Ang) II-induced inflammation in endothelial cells, this study was designed to investigate the role of SIRT1 and SIRT6 in CC-induced variation of ACE2 expression and the related mechanism between SIRT6 and ACE2. We found that ACE2 is involved in CC-induced endothelial dysfunction, which inhibits decreases in nitric oxide (NO) level and endothelial nitric oxide synthase (eNOS) activity and increases in inflammatory factors and adhesion molecules. Besides, SIRT1 and SIRT6 regulated the protein expression of ACE2 in CC-stimulated human umbilical vein endothelial cells (HUVECs). Moreover, bioinformatics analysis from the Enrichr database indicated that activating transcription factor 2 (ATF2), is highly correlated with genes that significantly upregulated after infection with the SIRT6 adenovirus vector. In CC-induced HUVECs, ACE2 expression was up-regulated in cells transfected with ATF2 siRNA. However, further mechanism studies revealed that overexpression of SIRT6 decreases the accumulation of p-ATF2 in the nucleus, but did not affect p-ATF2 expression in the cytoplasm. Taken together, these data indicated that SIRT6 regulates ACE2 might via inhibiting the accumulation of nucleus p-ATF2 in CC-induced endothelial dysfunction.

Outcomes following sacrocolpopexy using ultralight and lightweight mesh.

INTRODUCTION AND HYPOTHESIS: This study reports the long-term anatomic and subjective outcomes following sacrocolpopexy based on mesh weight and provides device-specific data. METHODS: This cohort study compared ultra-lightweight (≤ 20 g/m2) with lightweight mesh (≥ 25 g/m2). The primary outcome was composite failure defined as at least one of ≥ stage 2 apical prolapse, anterior or posterior vaginal wall beyond hymen, complaint of bulge or retreatment. Effect measure estimates were calculated as the incidence rate ratio of composite failure comparing the use of ultra-light with lightweight mesh. Crude and adjusted incidence rate ratios (IRRs) were obtained using uni- and multivariable Poisson regression models. RESULTS: Of 358 women who met inclusion criteria, 220 (61%) agreed to attend for review; 95 (43%) had ultra-lightweight mesh and 125 (57%) had lightweight mesh including UpsylonTM. Median follow-up for ultra-light and lightweight mesh was 36 (IQR 22-42) and 63 (IQR 48-87) months, respectively (p < 0.001). Accounting for differences in follow-up time, there was no significant difference in composite failure between ultra-light and lightweight mesh groups (IRR 1.47, 95% CI 0.83-2.52, p = 0.15). This persisted after adjustment for age, body mass index, parity, smoking and presence of advanced prolapse prior to surgery (IRR 1.52, 95% CI 0.94-2.47, p = 0.087). Mesh exposure for both groups was mostly asymptomatic, and the rate was 7% for the ultra-light group and 8% in the lightweight group. Overall, repeat surgery for recurrent apical prolapse and mesh exposure occurred in 4% and 2%, respectively. CONCLUSIONS: Ultra-lightweight mesh appears to have similar incidence rate of failure compared to lightweight mesh. UpsylonTM mesh has a similar low rate of recurrent apical prolapse and mesh exposure.

Improvement of Molecular Diagnosis Using Domain-Level Single-Nucleotide Variants by Eliminating Unexpected Secondary Structures.

Identification of single-nucleotide variants (SNVs) is of great significance in molecular diagnosis. The problem that should not be ignored in the identification process is that the unexpected secondary structure of the target nucleic acid may greatly affect the detection accuracy. Herein, we proposed a conditional domain-level SNV diagnosis strategy, in which the subsequent SNV detection can only be carried out after eliminating the unexpected secondary structure of target DNA. Specifically, the target DNA is assembled into a rigid double strand, which makes folding the target DNA difficult and the unexpected secondary structure is eliminated. Based on this double-stranded structure, specially designed probes are used to detect double-stranded properties and report abundant domain-level oligonucleotide information to improve the effective information in the detection results and complete domain-level SNV diagnosis. If the unexpected secondary structure is not eliminated, the detector will first detect it and feed back to us, ensuring the accuracy of the subsequent detection results. With the occurrence (or not) of SNV and the change of the SNV site, in the proof-of-concept experiment, we successfully identified the four homologous sequences to be tested related to BRAF gene.

Equipment-free photothermal effect promoted self-healing and self-recovery of hydrogels.

The self-healing and self-recovery of the hydrogel materials can be promoted under sunlight without the assistance of electrical equipment by adding a light-to-heat conversion substance during the synthetic process, which will greatly extend the service life of the hydrogels even for the elastomer materials in the off-grid areas.

Changes in the modes of twin birth in Victoria, 1983-2015.

OBJECTIVES: To examine changes in the modes of delivery of twins in Victoria over 33 years. DESIGN: Retrospective population-based study. SETTING, PARTICIPANTS: All twin births in Victoria, 1 January 1983 - 31 December 2015. MAJOR OUTCOMES: Mode of birth (vaginal, planned or unplanned caesarean delivery); indications for caesarean delivery. RESULTS: During 1983-2015, 32 187 twin pregnancies ended in live or stillbirths in Victoria. The proportion of twins born by caesarean delivery increased from 24% (156 twin deliveries) in 1983 to 71% (782 deliveries) in 2015. The proportion of twin births by planned caesarean delivery with twin pregnancy as the sole indication for caesarean delivery increased across this period from 1.8% (12 twin deliveries) to 21% (231 deliveries). The proportion of twin births by caesarean delivery and the proportion of caesarean twin deliveries with twin pregnancy as the principal indication each differed between Victorian regions. CONCLUSION: During 1983-2015, the proportion of twins born in Victoria by caesarean delivery increased almost threefold, mostly because caesarean delivery has become the preferred mode of birth for twin pregnancies. Regional differences in the delivery of twins suggest that the number of caesarean deliveries can be reduced with appropriate system and training support.

Epigenetic abnormalities of classical Hodgkin lymphoma and its effect on immune escape.

Classical Hodgkin lymphoma (cHL) is a particular kind of malignant tumour that originates from the B cells. The malignant phenotype of cHL is, at least in part, maintained by epigenetic aberrations, which primarily consist of abnormal histone methylation and acetylation. Progress has been made in clinical trials concerning the histone deacetylases inhibitors (HDACis) in cHL. Also, some demethylation regimens could serve the purpose of preventing and treating tumours. Programmed death-ligand receptor 1 (PD-L1, CD274) inhibitors or apoptosis receptor 1 (PD-1, CD279) inhibitors are used in treating patients with relapsed cHL in recent years. Academic researches indicated that PD-1/PD-L1 inhibitors, including nivolumab and pembrolizumab, demonstrate remarkable activity in relapsed cHL. In addition, in recent years, a close association between epigenetic aberrations and immune escape has been explored in cHL. DNA methyltransferase (DNMT) inhibitors, HDACis, and immune checkpoint blockade exhibit synergistic effects. Thus, this review aims to provide an overview on the epigenetic abnormalities of cHL and its effect on immune escape, in order to explore the optimal combination approach to treat the disease. SIGNIFICANCE OF THE STUDY: Cancer Statistics 2018 reported that more than 8000 new cases of Hodgkin lymphoma were diagnosed. In recent years, PD-1/PD-L1 inhibitors for cHL have been utilized, and the therapeutic strategies of HDACis combined with PD-1/PD-L1 inhibitors have been raised. It is critical for improving the efficacy and decreasing the toxicity in treating the patients with cHL.

Structural Characterization of a Boron(III) η2-σ-Silane-Complex.

Coordination of H-E (E = H, C, Si, etc.) σ-bonds to unsaturated element centers, forming η2-σ-complexes, is a crucial step in H-E bond activations which are involved in numerous chemical transformations. Structural characterization of σ-complexes has provided invaluable insight into the σ-bond activation process. While numerous η2-σ-complexes of low-oxidation-state transition metals have been isolated and thoroughly studied, those based on d0 metals or high-oxidation-state main group elements still remain elusive, despite their suggested role as key intermediates in σ-bond metathesis. Here we report the synthesis of a highly electrophilic o-carboranyl-substituted hydroborenium and its η2-σ-(H-Si)-complex, the latter of which was characterized by X-ray analysis. Unlike previous known σ-(H-Si)-complexes in which back-donation contributes significantly to their stability, our computational studies revealed that no back-donation takes place between the borenium and silane moieties, and the key factors for the stability of this silane-borenium complex are (1) the strong interaction between the empty p orbital of the boron center and the bonding σ orbital of H-Si and (2) steric accessibility of the boron center due to the presence of a hydrogen substituent.

Divergent Syntheses of Carbazole Alkaloids Clausenapin, Indizoline, Claulansine M, and Clausenaline D.

We described the first total syntheses of clausenapin, indizoline, claulansine M, and a novel synthetic route to clausenaline D via divergent method. Key steps involved TFAA-mediated intramolecular acylation to construct the carbazole core and subsequent Claisen rearrangement to generate key intermediates for further elaboration to target molecules.