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•Activating PK improved red cell integrity in SCD by reducing Tyr-p-bd3.•ATP plays a critical role in preventing the membrane-destabilizing effects of Tyr-p-bd3 by improving activity of constitutive phosphatase.

Tumor-associated macrophages (TAMs) are recognized as a hallmark of certain solid cancers and predictors of poor prognosis; however, the functional role of TAMs in lymphoid malignancies, including B-cell lymphoma, has not been well defined. We identified infiltration of F4/80+ TAMs in a syngeneic mouse model using the recently generated murine mantle cell lymphoma (MCL) cell line FC-muMCL1. Multicolor flow cytometric analysis of syngeneic lymphoma tumors showed distinct polarization of F4/80+ TAMs into CD206+ M2 and CD80+ M1 phenotypes. Using human MCL cell lines (Mino, Granta, and JVM2), we further showed that MCL cells polarized monocyte-derived macrophages toward an M2-like phenotype, as assessed by CD163+ expression and increased interleukin-10 (IL-10) level; however, levels of the M1 markers CD80 and IL-12 remained unaffected. To show that macrophages contribute to MCL tumorigenesis, we xenografted the human MCL cell line Mino along with CD14+ monocytes and compared tumor growth between these 2 groups. Results showed that xenografted Mino along with CD14+ monocytes significantly increased the tumor growth in vivo compared with MCL cells alone (P < .001), whereas treatment with liposomal clodronate (to deplete the macrophages) reversed the effect of CD14+ monocytes on growth of MCL xenografts (P < .001). Mechanistically, IL-10 secreted by MCL-polarized M2-like macrophages was found to be responsible for increasing MCL growth by activating STAT1 signaling, whereas IL-10 neutralizing antibody or STAT1 inhibition by fludarabine or STAT1 short hairpin RNA significantly abolished MCL growth (P < .01). Collectively, our data show the existence of a tumor microenvironmental network of macrophages and MCL tumor and suggest the importance of macrophages in interventional therapeutic strategies against MCL and other lymphoid malignancies.

Tumor-associated macrophages (TAMs) are recognized as a hallmark of certain solid cancers and predictors of poor prognosis; however, the functional role of TAMs in lymphoid malignancies, including B-cell lymphoma, has not been well defined. We identified infiltration of F4/80+TAMs in a syngeneic mouse model using the recently generated murine mantle cell lymphoma (MCL) cell line FC-muMCL1. Multicolor flow cytometric analysis of syngeneic lymphoma tumors showed distinct polarization of F4/80+TAMs into CD206+M2 and CD80+M1 phenotypes. Using human MCL cell lines (Mino, Granta, and JVM2), we further showed that MCL cells polarized monocyte-derived macrophages toward an M2-like phenotype, as assessed by CD163+expression and increased interleukin-10 (IL-10) level; however, levels of the M1 markers CD80 and IL-12 remained unaffected. To show that macrophages contribute to MCL tumorigenesis, we xenografted the human MCL cell line Mino along with CD14+monocytes and compared tumor growth between these 2 groups. Results showed that xenografted Mino along with CD14+monocytes significantly increased the tumor growth in vivo compared with MCL cells alone (P< .001), whereas treatment with liposomal clodronate (to deplete the macrophages) reversed the effect of CD14+monocytes on growth of MCL xenografts (P< .001). Mechanistically, IL-10 secreted by MCL-polarized M2-like macrophages was found to be responsible for increasing MCL growth by activating STAT1 signaling, whereas IL-10 neutralizing antibody or STAT1 inhibition by fludarabine or STAT1 short hairpin RNA significantly abolished MCL growth (P< .01). Collectively, our data show the existence of a tumor microenvironmental network of macrophages and MCL tumor and suggest the importance of macrophages in interventional therapeutic strategies against MCL and other lymphoid malignancies.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27(IPN60090), which is currently in phase 1 clinical trials. Compound 27attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

Supplemental Digital Content is available in the text.The development of immunotherapy has improved the treatment of melanoma; however, resistance and frequent recurrence persist and remain a major problem. N6-methyladenosine (m6A) is the most abundant epitranscriptomic mark on mRNA and is essential for various physiological processes; however, its role in melanoma is unknown. Utilizing human normal melanocyte and melanoma cell lines, we analyzed the expression of METTL3 by quantitative RT-PCR. We inhibited the METTL3 expression by shRNA and analyzed the effects on melanoma cell proliferation, colony formation ability, and invasion. Finally, we assessed the role of METTL3 by using wild-type and m6A catalytic site mutant METTL3. Melanoma cell lines express higher levels of METTL3, as compared with normal melanocytes. Interestingly, silencing of METTL3 gene expression in melanoma cells resulted in decreased m6A activity, colony formation and invasiveness, while its overexpression led to increased m6A activity, colony formation and invasion. METTL3 overexpression promotes accumulation of MMP2 and N-cadherin in melanoma cells. Strikingly, the overexpression of m6A catalytic site mutant METTL3 was unable to produce a similar increase in MMP2 expression, suggesting that m6A activity of METTL3 is important for melanoma cell invasiveness. Our results for the first time uncover the role of m6A modification in melanoma cell biology. We show that METTL3 is upregulated in human melanoma and plays a role in invasion/migration through MMP2. These findings provide the framework for the development and use of METTL3 inhibitors in melanoma treatment.

In a Phase I study (NCT04000165, Xu et al, 2022), we showed that mitapivat, an investigational oral allosteric activator of pyruvate kinase (PK), demonstrated an acceptable safety and tolerability profile at multiple ascending dose levels in patients (pts) with sickle cell disease (SCD). We also established proof-of-concept for activating PK as a viable therapeutic approach; mitapivat decreased 2,3- diphosphoglycerate (2,3-DPG) and increased adenosine triphosphate (ATP) levels, improved hematologic parameters, and reduced sickling in pts with SCD (HbSS). In this extension study (NCT04610866), we evaluated the safety, tolerability and efficacy of mitapivat as a long-term maintenance therapy for pts with SCD.

2,3-diphosphoglycerate (DPG) in red blood cells (RBCs) stabilizes deoxyhemoglobin to promote hemoglobin (Hb) oxygen off-loading and counteract hypoxia. In sickle cell disease (SCD), mutation of glutamate 6 to valine in the beta chain of Hb results in HbS that polymerizes, causing RBCs to sickle upon deoxygenation in the tissues. Elevated DPG promotes sickling by stabilizing HbS fibers. DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (PK) is a rate-limiting enzyme. In a previous Phase 1 study (NCT04000165, Xu et al, 2022), we established proof-of-concept for activating PK as a viable anti-sickling therapeutic approach; mitapivat, an investigational oral allosteric activator of PK, decreased DPG and increased adenosine triphosphate (ATP) levels, improved hematologic and sickling parameters in patients (pts) with SCD (HbSS). Here, we investigated the changes in the metabolome, lipidome and proteome of RBCs from patients with SCD currently enrolled in an open label, Phase 1/2 study (NCT04610866) that evaluates long-term safety and tolerability of mitapivat in pts with SCD.

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BACKGROUND:

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

•CCR1, expressed on macrophages, promotes macrophage migration and M2-polarization via tumor-derived CCL3.•CCR1 inhibition exerts antilymphoma activity by reprogramming macrophages.

According to the resonant characteristics of piezoelectric materials, in order to get the parameters of piezoelectric materials under DC bias voltage by calculate the impedance spectrum of piezoelectric materials, and the changes of the parameters of piezoelectric materials under DC bias were discussed. This paper measured the impedance spectrum of piezoelectric materials under different DC bias voltage with TH2828S Impedance Analyzer, and found that DC bias voltage made the material impedance spectrum drifted. Various parameters of materials were calculated by the resonance method, it was found that the parameters of piezoelectric materials under varied bias voltage were different, and the behaviours of each parameters under DC bias voltage were obtained.It was consider that the elastic constant and dielectric constant were changed due to the inverse piezoelectric effect of the piezoelectric materials which were under DC bias voltage,so that other parameters were changed.Then the resonant frequent formula of piezoelectric materials under DC bias voltage was deduced.

As same as the traditional application and system software, firmware also faced the risk of malicious code like hobbyhorse, back door, logical bomb and so on. Firmware exhibited strong cohesion and hardware relativity, which make the malicious action in firmware to be different from that in the traditional software. This paper analyzed the specificities of firmware and the malicious behaviour about it, then expatiate the essence of the malicious behaviour of the firmware, and presented a firmware formal definition and detecting method which was based on the hardware resources access control policy. Experimental results proved that the method was effective to detect the malicious firmware.

No relevant conflicts of interest to declare.

Graft versus host disease (GVHD) continues to be a life-threatening complication of stem cell transplantation for hematological malignancies. GVHD occurs in perfectly HLA-matched, related (MRD) transplants, and conversely can be absent in matched un-related (MUD) or haploidentical stem cell transplants (SCT). Minor histocompatibility antigens (mHA) have been investigated for their contribution to GVHD in SCT, which is mediated by differential presentation of these antigens in the recipient tissues to the donor derived T cells. Our group and others have shown that predicted mHA in bone marrow transplant donor-recipient pairs (DRP) range in the 1,000s, with MUD on the average having 2x as many mHA as MRD. However, repeated studies have shown that absolute number of mHA does not correlate with GVHD - that is more minor histocompatibility antigens do not lead to higher rates of GVHD. It is unknown if the tissue distribution of mHA in SCT differs significantly between patients, and what role this may have in the biology of GVHD. Therefore, our group investigated if the distribution of in silicoderived mHA might correlate with GVHD occurrence. Whole exome sequencing (WES) of 77 HLA matched SCT DRP was performed and revealed thousands of nucleotide polymorphisms unique to the recipient when compared with the donor. When translated into peptide fragments and queried for binding to HLA-A, B, and C, in each DRP, these polymorphic peptides generated thousands of putative mHA/DRP in silico. Lists with the genes of origin for the mHA were then compiled for each DRP and sorted by the binding affinity of polymorphic recipient peptides to HLA; presented binders (IC50<500, termed “PB”) and strong binders (IC50<50, termed “SB”) numbered in the hundreds and were considered further.

The release rhythm of volatiles is an important physiological characteristic of plants, because the timing of release can affect the function of each particular volatile compound. However, most studies on volatiles release rhythms have been conducted using model plants, rather than crop plants. Here, we analyzed the variations in volatile compounds released from healthy and leafminer (Liriomyza huidobrensis)-infested kidney bean (Phaseolus vulgaris), an important legume crop plant, over a 24 h period. The constituents of the volatiles mixture released from plants were analyzed every 3 h starting from 08:00. The collected volatiles were identified and quantified by gas chromatography–mass spectrometry. Undamaged kidney bean plants released trace amounts of volatiles, with no obvious release rhythms. However, leafminer-damaged plants released large amounts of volatiles, in two main peaks. The main peak of emission was from 17:00 to 20:00, while the secondary peak was in the early morning. The terpene volatiles and (Z)-3-hexenyl acetate showed similar rhythms as that of total volatiles. However, the green leaf volatile (Z)-3-hexen-ol was emitted during the night with peak emission in the early morning. These results give us a clear picture of the volatiles release rhythms of kidney bean plants damaged by leafminer.

The migratory locust, Locusta migratoria L., has one to four generations per year in China, overwintering as eggs in the soil. In temperate Hebei province, this species has two generations per year, known as the summer and fall generations. In this study, locust populations occurring in different seasons were compared to investigate the adaptation of eggs to a cold environment. Large seasonal variations were observed in the supercooling point (SCP) and lower lethal temperature (Ltemp50, the temperature that causes 50% mortality in a population) of locust eggs. Mean SCP values of the fall population were -26.0 ± 0.1°C, while those of the summer and postwinter populations were -22.0 ± 0.8 and -23.4 ± 0.7°C, respectively. The fall population also had significantly lower Ltemp50 values (-14.2°) than the summer (-4.8°) and postwinter populations (-6.7°C). The survival ability of eggs at different development stages was also compared; 10-d-old eggs incubated at 25°C were more cold hardy than other stages. Prechilling at 5°C was effective in increasing the cold hardiness of eggs. These results confirm that eggs of the fall population are better conditioned for overwintering. The low mortality of overwintering eggs often leads to high population density and serious crop damage in the next season or following year.

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