Maternal supplementation with konjac glucomannan improves maternal microbiota for healthier offspring during lactation.

BACKGROUND: The maternal diet during gestation and lactation affects the health of the offspring. Konjac glucomannan (KGM) is a significantly functional polysaccharide in food research, possessing both antioxidant and prebiotic properties. However, the mechanisms of how KGM regulates maternal nutrition remain insufficient and limited. This study aimed to investigate maternal supplementation with KGM during late gestation and lactation to benefit both maternal and offspring generations. RESULTS: Our findings indicate that KGM improves serum low density lipoprotein cholesterol (LDL-C) and antioxidant capacity. Furthermore, the KGM group displayed a significant increase in the feed intake-related hormones neuropeptide tyrosine (NPY), Ghrelin, and adenosine monophosphate-activated kinase (AMPK) levels. KGM modified the relative abundance of Clostridium, Candidatus Saccharimonas, unclassified Firmicutes, and unclassified Christensenellaceae in sow feces. Acetate, valerate, and isobutyrate were also improved in the feces of sows in the KGM group. These are potential target bacterial genera that may modulate the host's health. Furthermore, Spearman's correlation analysis unveiled significant correlations between the altered bacteria genus and feed intake-related hormones. More importantly, KGM reduced interleukin-6 (IL-6) levels in milk, further improved IL-10 levels, and reduced zonulin levels in the serum of offspring. CONCLUSION: In conclusion, maternal dietary supplementation with KGM during late gestation and lactation improves maternal nutritional status by modifying maternal microbial and increasing lactation feed intake, which benefits the anti-inflammatory capacity of the offspring serum. © 2024 Society of Chemical Industry.

Genotype and environment factors driven licorice growth and rhizospheric soil fungal community changes.

Introduction: Licorice (Glycyrrhiza uralensis Fisch.) is a widely recognized significant form of medicine in China, with a long-standing history and extensive usage. It is considered the oldest and most prevalent herbal medicine in China. Currently, the licorice market is confronted with the primary challenges of mixed genotypes, inconsistent quality, and inadequate glycyrrhizic acid content. Methods: We conducted field experiments to investigate the impact of various cultivation locations on the growth characteristics, active ingredients, rhizospheric soil physicochemical properties and fungal communities of licorice that ten different genotypes. Results: The findings indicated significant variations in these parameters across ten different genotypes of licorice originating from two distinct production regions. The growth characteristics of licorice were primarily influenced by genotype, whereas the active ingredients of licorice were mainly influenced by environmental factors and soil physicochemical properties. Furthermore, the rhizospheric soil physicochemical properties of licorice plants were more influenced by environmental factors than genotypes. Additionally, the distribution of rhizospheric soil fungi in licorice plants of the same genotype exhibited significant variations across different cultivation areas. The utilization of structural equation model synthesis reveals variations in the quantity and strength of pathways that influence the growth characteristics, active ingredients, and rhizospheric soil microbial community of licorice across different cultivation regions. Discussion: Based on the main results, according to its growth characteristics and active ingredients, Z009 proved to be the most suitable genotype for cultivation in Jingtai. From a perspective centered on the active ingredient, Z010 proved to be the most optimal genotype for licorice cultivation in both production areas. Our study aims to enhance the understanding of the ecological adaptability of various genotypes of licorice resources and to identify appropriate licorice genotypes for specific cultivation regions. This research holds significant practical implications for enhancing the yield and quality of licorice, thereby improving its overall development.

Oxidized Soybean Oil Evoked Hepatic Fatty Acid Metabolism Disturbance in Rats and their Offspring.

The oxidation of fats and oils is an undisputed subject of science, given the effect of oxidized fats and oils on food quality and safety. This study aimed to determine whether maternal exposure to oxidized soybean oil (OSO) causes lipid metabolism disorders in the liver and whether this lipid metabolism disorder can be transmitted to offspring or even worsened. A total of 60 female Sprague-Dawley (SD) rats were divided randomly into four groups in this study. Treatment groups received a pure diet of OSO with a peroxide value of 200, 400, or 800 mEqO2/kg, while the control group received fresh soybean oil (FSO). As for our results, OSO affected serum biochemical parameters in the maternal generation (F0) and induced liver histopathology changes, inflammation, and oxidative stress. Moreover, the expression of genes related to the liver X receptor α (LXRα)─sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway was changed. Similar trends were found in the livers of offspring on postnatal days 21 and 56. In conclusion, exposure to OSO during gestation and lactation can affect liver lipid synthesis. Additionally, it is detrimental to the development of the offspring's liver, affecting fatty acid metabolism and causing liver damage.

Preparation of thrombin-loaded calcium alginate microspheres with dual-mode imaging and study on their embolic properties in vivo.

Transcatheter arterial embolization (TAE) has played a huge role in the interventional treatment of organ bleeding and accidental bleeding. Choosing bio-embolization materials with good biocompatibility is an important part of TAE. In this work, we prepared a calcium alginate embolic microsphere using high-voltage electrostatic droplet technology. The microsphere simultaneously encapsulated silver sulfide quantum dots (Ag2S QDs) and barium sulfate (BaSO4), and fixed thrombin on its surface. Thrombin can achieve an embolic effect while stopping bleeding. The embolic microsphere has good near-infrared two-zone (NIR-II) imaging and X-ray imaging effects, and the luminous effect of NIR-II is better than that of X-rays. This breaks the limitations of traditional embolic microspheres that only have X-ray imaging. And the microspheres have good biocompatibility and blood compatibility. Preliminary application results show that the microspheres can achieve a good embolization effect in the ear arteries of New Zealand white rabbits, and can be used as an effective material for arterial embolization and hemostasis. This work realizes the clinical embolization application of NIR-II combined with X-ray multimodal imaging technology in biomedical imaging, achieving complementary advantages and excellent results, more suitable for studying biological changes and clinical applications.

Deciphering the effects of genotype and climatic factors on the performance, active ingredients and rhizosphere soil properties of Salvia miltiorrhiza.

Introduction: Salvia miltiorrhiza Bunge is an important medicinal herb, which is widely cultivated in most parts of China. It has attracted considerable attention because of its pharmacological properties and potential health benefits. Methods: We used a field experiment to determine the effects of different genotypes and climatic factors on the performance (plant biomass, morphological parameters), active ingredients, rhizosphere soil physicochemical properties and microbial composition of S. miltiorrhiza at five cultivation locations. Results: The results showed that these parameters were significantly different in the six different genotypes of S. miltiorrhiza from five producing areas. Genotype and soil physicochemical properties were the main factors affecting the growth traits of S. miltiorrhiza, while genotype, climate and soil physicochemical properties were the main factors affecting the content of active components of S. miltiorrhiza. Microbial phospholipid fatty acid analysis showed that the biomass of Gram-positive and Gram-negative bacteria was affected by the genotypes of S. miltiorrhiza plants, while the biomass of arbuscular mycorrhizal fungi, fungi, Gram-positive and Gram-negative bacteria was affected by climate factors. Discussion: Based on the main results, DS993 was the most suitable genotype for S. miltiorrhiza in the five producing areas from the perspective of comprehensive growth traits and medicinal components, while DS993 and DS2000 were suitable for planting in Shandong province from the perspective of origin. DS996 is not suitable for all of the above production areas. These results are helpful to understand the ecological adaptability of different genotypes of S. miltiorrhiza resources, and to select appropriate S. miltiorrhiza genotypes for specific planting areas, so as to maximize yield and quality.

Influence of Vitamin D supplementation on reproductive outcomes of infertile patients: a systematic review and meta-analysis.

BACKGROUND: Low vitamin D status has been associated with an increased risk for infertility. Recent evidence regarding the efficacy of vitamin D supplementation in improving reproductive outcomes is inconsistent. Therefore, this systematic review was conducted to investigate whether vitamin D supplementation could improve the reproductive outcomes of infertile patients and evaluate how the parameters of vitamin D supplementation affected the clinical pregnancy rate. METHODS: We searched seven electronic databases (CNKI, Cqvip, Wanfang, PubMed, Medline, Embase, and Cochrane Library) up to March 2022. Randomized and cohort studies were collected to assess the reproductive outcomes difference between the intervention (vitamin D) vs. the control (placebo or none). Mantel-Haenszel random effects models were used. Effects were reported as odds ratio (OR) and their 95% confidence interval (CI). PROSPERO database registration number: CRD42022304018. RESULTS: Twelve eligible studies (n = 2352) were included: 9 randomized controlled trials (RCTs, n = 1677) and 3 cohort studies (n = 675). Pooled results indicated that infertile women treated with vitamin D had a significantly increased clinical pregnancy rate compared with the control group (OR: 1.70, 95% CI: 1.24-2.34; I2 = 63%, P = 0.001). However, the implantation, biochemical pregnancy, miscarriage, and multiple pregnancy rates had no significant difference (OR: 1.86, 95% CI: 1.00-3.47; I2 = 85%, P = 0.05; OR: 1.49; 0.98-2.26; I2 = 63%, P = 0.06; OR: 0.98, 95% CI: 0.63-1.53; I2 = 0%, P = 0.94 and OR: 3.64, 95% CI: 0.58-11.98; I2 = 68%, P = 0.21). The improvement of clinical pregnancy rate in the intervention group was influenced by the vitamin D level of patients, drug type, the total vitamin D dosage, the duration, administration frequency, and daily dosage of vitamin D supplementation. The infertile women (vitamin D level < 30 ng/mL) treated with the multicomponent drugs including vitamin D (10,000-50,000 IU or 50,000-500,000 IU), or got vitamin D 1000-10,000 IU daily, lasting for 30-60 days could achieve better pregnancy outcome. CONCLUSION: To the best of our knowledge, this is the first meta-analysis systematically investigated that moderate daily dosing of vitamin D supplementation could improve the clinical pregnancy rate of infertile women and reported the effects of vitamin D supplementation parameters on pregnancy outcomes. A larger sample size and high-quality RCTs are necessary to optimize the parameters of vitamin D supplementation to help more infertile patients benefit from this therapy.

Lavender essential oil fractions alleviate sleep disorders induced by the combination of anxiety and caffeine in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Lavender (Lavandula angustifolia Mill.) essential oil is renowned for its use in the treatment of insomnia and mental disorder diseases in folk medicine. Previous pharmacological studies have also shown that lavender essential oil displays sedative and hypnotic activities. However, the active ingredients and mechanism of lavender essential oil for sleep-improving effect remain unclear. AIM OF THE STUDY: This study investigates whether inhalation of different fractions of lavender essential oil can attenuate the sleep disturbances induced by combined anxiety and caffeine and explores the underlying mechanisms. MATERIALS AND METHODS: Molecular distillation was applied to separate lavender essential oil into fractions containing different chemical components, and GC-MS was used to analyze the volatile compounds of lavender essential oil and its fractions. The elevated plus maze test, pentobarbital-induced sleep test, and neurotransmitters enzyme-linked immunosorbent assay were conducted to evaluate the anxiolytic and hypnotic effects of lavender essential oil and its fractions on mice suffering from sleep disorders. RESULTS: The results of behavioral tests indicated that lavender essential oil and its fractions (3%, v/v) exerted an ameliorating effect on sleep disturbances induced by anxiety and caffeine. The light fraction and heavy fractions exhibited complementary chemical composition, with the former enriched in linalool and trans-ß-ocimene and the latter in linalyl acetate, lavandulyl acetate, trans-caryophyllene, etc. The light fraction contributed more to sleep maintenance, and the heavy fraction performed better at sleep initiation. The neurobiological parameters elucidated that the mechanism of lavender essential oil for sleep-improving was multifaceted, related to the GABAergic system, cholinergic system, histaminergic system, and monoamines in the limbic system. The heavy fraction shared a similar mechanism with the lavender essential oil, while the light fraction did not actively participate in the cholinergic system, histaminergic system, and dopaminergic system. CONCLUSION: Taken together, our results demonstrated that different fractions of lavender essential oil played different roles in ameliorating sleep disorders, and this may be credited to their compositional differences and the complicated interactions with the central nervous system. The results are informative for future investigations on the molecular level mechanisms and provide guidance for appropriate applications of lavender essential oil.

A comprehensive review on ethnobotanical, phytochemical and pharmacological aspects of Rhus chinensis Mill.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhus chinensis Mill., firstly recorded as herbal medicine in Shan Hai Jing, have been used for thousands of years to treat various diseases. AIM OF THIS REVIEW: This review targets on the ethnomedicinal applications of R. chinensis and to gather the phytochemical, pharmacological and toxicological data which support the therapeutic potential of R. chinensis in treatment on different diseases, with emphasis on the naturally occurring compounds and detailed pharmacological developments. MATERIALS AND METHODS: The information of R. chinensis was collected based on a variety of popular databases such as Scifinder, PubMed, Web of Science, ScienceDirect, Springer, Wiley, ACS, CNKI, Baidu Scholar, Google Scholar and other published materials (books and Ph.D. and M. Sc. Dissertations). The keywords "Rhus chinensis", "Rhus amela", "Rhus javanica", "Rhus osbeckii", "Rhus semialata", and "Schinus indicus" were applied to search the literature related in this review. RESULTS: 152 natural compounds of R. chinensis belong to different classes are presented in this review, including flavonoids, lignans, coumarins, simple phenolics, urushiols, tannins, triterpenoids, steroids and other types of constituents. Among them, flavonoids, lignans, and triterpenoids are most frequently reported components. The pharmacological effects of R. chinensis were numerous and complicated, including anti-viral, anti-bacterial, anti-diarrheal, hepatoprotective, anti-proliferation, enzyme-inhibiting, anti-oxidants and so on. CONCLUSION: In order to discover more compounds with novel structures to both enrich chemical context of genus Rhus and expand the variety of constituents, the phytochemical research is urgent and indispensable. Anti-diarrhea, the most widely application of R. chinensis traditionally, is insufficient in underlying mechanism exploration. And for other activities, in-depth studies on the mechanism of pharmacological effects in vivo and in vitro are both needed. Meanwhile, pharmacokinetics, toxicology, quality control and preclinical and clinical data are urgent to assess the rationale and safety of the medicinal and food application of R. chinensis.

Semiconductor small molecule IHIC/ITIC applied to photothermal therapy and photoacoustic imaging of tumors.

Organic semiconductor small molecules IHIC and ITIC have been developed as solar cell materials, and because of their strong near-infrared absorption capabilities, they are promising for cancer phototherapy. This article reports the application of semiconductor small molecule IHIC/ITIC liposomes in photothermal therapy and photoacoustic imaging of tumors firstly. Experiments show that the liposome-loaded IHIC/ITIC material has good biocompatibility and can be effectively enriched in tumor sites. After being irradiated with laser, it can emit strong photoacoustic signals, and has achieved good results in the photothermal treatment of breast cancer mice. We believe that organic semiconductor small molecule IHIC/ITIC will become a promising photothermal agent with wonderful development possibilities.

Ginsenoside Rg3 Reduces Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-ß1 by Inactivation of AKT in HMrSV5 Peritoneal Mesothelial Cells.

BACKGROUND Ginsenosides, including ginsenoside Rg3, are components of Panax ginseng C.A. Meyer (Araliaceae) used in traditional Chinese medicine. Long-term peritoneal dialysis induces peritoneal fibrosis that impairs ultrafiltration and is associated with epithelial-mesenchymal transition (EMT) of peritoneal cells. This study aimed to investigate the effects of ginsenoside Rg3 on EMT induced by transforming growth factor-ß1 (TGF-ß1) in HMrSV5 human peritoneal mesothelial cells. MATERIAL AND METHODS The cell counting kit-8 (CCK-8) assay measured HMrSV5 cell viability. The expression of EMT markers, E-cadherin, vimentin, and alpha-smooth muscle actin (alpha-SMA) were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The wound-healing assay determined cell migration. The S-phase of the cell cycle was assessed by 5-ethynyl-2'-deoxyuridine (EdU) labeling, and expression of phosphorylated AKT was measured by Western blot. The effect of ginsenoside Rg3 and the AKT activator SC79 on the TGF-ß1-induced EMT of HMrSV5 cells were evaluated. RESULTS Low concentration of ginsenoside Rg3 did not effect cell viability of HMrSV5 cells. TGF-ß1 treatment decreased the expression of E-cadherin, and increased the expression of vimentin and alpha-SMA and promoted cell migration of HMrSV5 cells. However, co-treatment of ginsenoside Rg3 and TGF-ß1 significantly reduced TGF-ß1-induced EMT in HMrSV5 cells. TGF-ß1 increased the phosphorylation of AKT and increased the expression of Smurf2. Ginsenoside Rg3 reduced TGF-ß1-induced activation of AKT and Smurf2. SC79 reversed the effects of ginsenoside Rg3 on TGF-ß1-induced EMT in HMrSV5 cells. CONCLUSIONS Ginsenoside Rg3 inhibited EMT induced by TGF-ß1 in HMrSV5 human peritoneal mesothelial cells by inhibiting the activation of AKT.

Nutrient release from fish cage aquaculture and mitigation strategies in Daya Bay, southern China.

Finfish cage culture is the most predominant form of mariculture. The rapid expansion of fish cage culture systems has raised concerns about their environmental impact, such as nutrient release. In this study, for the first time, we estimated the release of nitrogen (N) and phosphorus (P) from fish cage culture in Daya Bay, southern China, by constructing N and P budget models based on a mass balance principle. In addition, the contribution and importance of nutrients from fish culture and other nutrient sources, including submarine groundwater discharge, benthic sediments, local rivers, and atmospheric deposition were assessed. The annual amount of N and P released from fish cage culture was 205.6 metric tons (hereafter tons) of N and 39.2 tons of P, including 142.7 tons of dissolved inorganic nitrogen (DIN) and 15.1 tons of dissolved inorganic phosphorus (DIP). Among the analyzed nutrient sources, the contributions of DIN and DIP from fish culture were 7.0% and 2.7%, respectively. For cages consuming conventional trash fish, 142 kg of N and 26 kg of P were released into the environment per ton of fish products, much higher than the values (72 kg N and 17.3 kg P) for cages using formulated feed. In fish culture, the dissolved nutrients were more N rich, but the particulate nutrients were more P rich. The ratio of cage-derived N and P was 21.1, higher than the ratio of coastal seawater (27.1), indicating that cage culture may also impact the local nutrient forms around farming regions. Oyster cultivation and harvest removed 126.3 tons of N and 35.1 tons of P from of the bay. Replacing trash fish with formulated feed and co-culturing of nutrient extractive species (e.g., bivalves, macroalgae) and deposit-feeding species (e.g., sea cucumber) in fish culture zones can be efficient nutrient mitigation strategies.

A review of the application of near-infrared spectroscopy to rare traditional Chinese medicine.

Near-infrared spectroscopy (NIRS) has become popular in the field of traditional Chinese medicine (TCM) due to its many practical advantages, such as providing rapid, accurate, and simultaneous analysis. This review is intended to provide up-to-date information on qualitative and quantitative NIRS analysis in TCM, especially rare TCM. By performing a substantial survey of the literature from China and abroad, we also combine our own studies on some rare TCMs using NIRS to review the application of NIRS in this field. Basic analytical methods and specific examples of NIRS demonstrates NIRS's ability in authenticity identification, species identification, geographic origin analysis, quantitative analysis, adulteration detection, rapid detection, and on-line monitoring of TCM, and illustrates the feasibility and effectiveness of NIRS applied in the quality control (QC) of TCM. Some disadvantages and prospects of NIRS are also discussed here in detail.

Preferred Magnetic Excitations in the Iron-Based Sr_{1-x}Na_{x}Fe_{2}As_{2} Superconductor.

With spin-orbit coupling, both local-moment magnetism and itinerant electrons are expected to behave anisotropically in spin space, but such effects' influence on the formation of unconventional superconductivity has been hitherto unexplored. Here, in an iron-based superconductor, Sr_{1-x}Na_{x}Fe_{2}As_{2}, we report spectroscopic evidence that itinerant electrons "prefer" to be assisted by c-axis polarized magnetic excitations in their formation of superconducting Cooper pairs, against the polarization of the local-moment excitations. Our result naturally explains why the superconductivity competes strongly with the tetragonal magnetic phase in this material, and provides a fresh view on how to make a good superconductor out of a magnetic "Hund's metal."

The Enhanced International Prognostic Index for Diffuse Large B-cell Lymphoma.

OBJECTIVE: To explore the prognostic value of the enhanced International Prognostic Index (NCCN-IPI) for Asian patients with diffuse large B-cell lymphoma (DLBCL) treated in the rituximab era. MATERIALS AND METHODS: We performed a retrospective analysis of 176 patients with newly diagnosed DLBCL. The estimated overall survival (OS) and progression-free survival (PFS) of the different risk groups were discriminated by the International Prognostic Index (IPI), the revised International Prognostic Index (R-IPI) and the NCCN-IPI. RESULTS: With a median follow-up of 18 months, at 3 years, the OS was 73% and the PFS was 65%. The 3-year OS for the 4 NCCN-IPI risk groups were 91% versus 80% versus 57% versus 45% (P < 0.001); the 3-year PFS were 77% versus 72% versus 56% versus 26% (P < 0.001). The 3-year OS of the 4 risk groups discriminated by the IPI ranged from 85-55% (P < 0.001); the 3-year PFS ranged from 81-41% (P < 0.001). The 3-year OS of the 3 distinct prognostic groups by the R-IPI ranged from 86-51% (P < 0.001); the 3-year PFS ranged from 86-47% (P < 0.001). The 3-year OS and PFS of the high-risk group according to the NCCN-IPI were lower than the IPI and R-IPI. Using the NCCN-IPI, the outcomes among the risk groups spanned a large range, and the survival of the high-risk group was significantly different from the high-intermediate risk group. CONCLUSIONS: The NCCN-IPI is a clinically useful prognostic index for patients with DLBCL treated in the rituximab era, especially for high-risk patients.

Modulation of plasminogen activator inhibitor-1 (PAI-1) by the naphthoquinone shikonin.

Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. Elevated levels of PAI-1 are associated with thrombosis and cardiovascular and metabolic diseases. Inhibition of PAI-1 activity represents a new strategy for antithrombotic and antifibrinolysis therapies. In this study, we systematically investigated the inhibitory effect of shikonin on PAI-1 activity. In the chromogenic substrate-based urokinase (uPA)/PAI-1 assay, we found that shikonin inhibited human PAI-1 activity with IC50 values of 30.68±2.32µM. This result was further confirmed by urokinase-type plasminogen activator (uPA)-mediated clot lysis assay. Mechanistic studies indicated that shikonin directly could bind to PAI-1 and prevent the binding of PAI-1 to uPA in a dose-dependent manner. Shikonin also blocked the formation of PAI-1/uPA complex, as shown by SDS/PAGE analysis. In the mouse arterial thrombosis model, intraperitoneal injection of shikonin at 1mgkg(-1) dose significantly prolonged tail bleeding time from 12.956±4.457min to 26.576±2.443min. It also reduced arterial thrombus weight from 0.01±0.001g to 0.006±0.001g (p<0.05). In a liver fibrosis treatment model, when shikonin was continuously injected intraperitoneally at a dose of 1mgkg(-1) over a two-week period, the hydroxyproline content in the mice plasma was significantly reduced and the degree of liver fibrosis was decreased significantly. Thus, shikonin may represent a novel small molecule inhibitor of PAI-1 that could have become a lead drug the treatment of thrombus and fibrosis.

Role of chemokines and their receptors in chronic lymphocytic leukemia: function in microenvironment and targeted therapy.

Chemokines produced in distinct tissue microenvironments sustain migration of mature lymphocytes in lymphoglandula. Chemokine receptors expressed on chronic lymphocytic leukemia (CLL) cells regulate the migration of the leukemia cells within the bone marrow (BM), lymphoid organs in collaboration with chemokines. Chemokines form a pro-survival circuitry by regulating leukocyte trafficking, maintaining extended lymphocyte survival. Therefore, chemokines in tumor cell-microenvironment interactions represent a target for treatment of CLL. AMD3100 disrupts the CLL/microenvironment interactions and influences CXCL12/CXCR4 survival signaling. Fostamatinib, ibrutinib, and GS-1101 as B-cell receptor (BCR)-related kinase inhibitors inhibit BCR- and chemokine-receptor-signal-regulated kinase and have a good clinical response in CLL. Lenalidomide, sorafenib, and dasatinib are other additional drugs associated with chemokine in microenvironment. Inhibiting signaling through chemokine and microenvironment associated signaling are emerging as innovative therapeutic targets in CLL. In this article, we reviewed the role of chemokines in CLL microenvironment and novel therapeutics targeting CLL microenvironment.