Interaction between caffeine consumption & genetic susceptibility in Parkinson's disease: A systematic review.

BACKGROUND: Caffeine is one of the most consumed psychoactive substances globally. Caffeine-gene interactions in Parkinson's disease (PD) has not been systematically examined. OBJECTIVES: To conduct a systematic review on the interaction between caffeine consumption and genetic susceptibility to PD. METHODOLOGY: We conducted PubMed and Embase search using terms "Genetic association studies", "Caffeine", "polymorphism" and "Parkinson's disease", from inception till 2023. Of the initial 2391 studies, 21 case-control studies were included. The demographic, genetic and clinical data were extracted and analyzed. RESULTS: We identified 21 studies which involved a total of 607,074 study subjects and 17 gene loci (SNCA, MAPT, HLA-DRA, NOS1, NOS3, GBA, ApoE, BST1, ESR2, NAT2, SLC2A13, LRRK2, NOS2A, GRIN2A, CYP1A2, ESR1, ADORA2A) have been investigated for the effect of gene-caffeine interaction and PD risk. The genes were identified through PD GWAS or involved in caffeine or related metabolism pathways. Based on the genetic association and interaction studies, only MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A have been shown by at least one study to have a positive caffeine-gene interaction influencing the risk of PD. CONCLUSION: Studies have shown an interaction between caffeine with genetic variants of MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A in modulating the risk of PD. Due to the potential limitations of these discovery/pilot studies, further independent replication studies are needed. Better designed genetic association studies in multi-ancestry and admixed cohorts to identify potential shared or unique multivariate gene-environmental interactions, as well as functional studies of gene-caffeine interactions will be useful.

Inhibitory modulation of action potentials in crayfish motor axons by fluoxetine.

The goal of this report is to explore how K2P channels modulate axonal excitability by using the crayfish ventral superficial flexor preparation. This preparation allows for simultaneous recording of motor nerve extracellular action potentials (eAP) and intracellular excitatory junctional potential (EJP) from a muscle fiber. Previous pharmacological studies have demonstrated the presence of K2P-like channels in crayfish. Fluoxetine (50 µM) was used to block K2P channels in this study. The blocker caused a gradual decline, and eventually complete block, of motor axon action potentials. At an intermediate stage of the block, when the peak-to-peak amplitude of eAP decreased to ∼60%-80% of the control value, the amplitude of the initial positive component of eAP declined at a faster rate than that of the negative peak representing sodium influx. Furthermore, the second positive peak following this sodium influx, which corresponds to the after-hyperpolarizing phase of intracellularly recorded action potentials (iAP), became larger during the intermediate stage of eAP block. Finally, EJP recorded simultaneously with eAP showed no change in amplitude, but did show a significant increase in synaptic delay. These changes in eAP shape and EJP delay are interpreted as the consequence of depolarized resting membrane potential after K2P channel block. In addition to providing insights to possible functions of K2P channels in unmyelinated axons, results presented here also serve as an example of how changes in eAP shape contain information that can be used to infer alterations in intracellular events. This type of eAP-iAP cross-inference is valuable for gaining mechanistic insights here and may also be applicable to other model systems.

Targeting IL-11R/EZH2 signaling axis as a therapeutic strategy for osteosarcoma lung metastases.

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling. We used shRNA to deplete IL-11Rα from OS cells; as a complementary approach, we added IL-11 exogenously to OS cells. The resulting changes in gene expression identified EZH2 as a downstream candidate. This was confirmed by knockdown of IL-11Rα in OS cells, which led to increased expression of genes repressed by histone methyltransferase EZH2, including members of the WNT pathway, a known target pathway of EZH2. Exogenous IL-11 increased the global levels of histone H3 lysine 27 trimethylation, evidence of EZH2 activation. Treatment with the EZH2 inhibitor GSK126 significantly reduced in vitro proliferation and increased cell-cycle arrest and apoptosis, which were partially mediated through the WNT pathway. In vivo, treatment of an orthotopic nude mouse model of OS with GSK126 inhibited lung metastatic growth and prolonged survival. In addition, significantly shorter recurrence-free survival was seen in OS patients with high levels of EZH2 in their primary tumors (P < .05). This suggests that IL-11Rα promotes OS lung metastasis via activation of EZH2. Thus, blocking EZH2 activity may be an effective strategy for inhibiting OS lung metastasis and improving prognosis.

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.

The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia.

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.

Characteristics and outcomes of acute myeloid leukaemia patients with baseline CD7 expression.

Targeted therapy development for acute myeloid leukaemia (AML) requires an understanding of specific expression profiles. We collected flow cytometry data on 901 AML patients and recorded aberrant CD7 expression on leukaemic blasts. 263 (29.2%) had blasts positive for CD7. CD7+ AML was more likely to be adverse risk (64.6% vs. 55.6%, p = 0.0074) and less likely to be favourable risk (15.2% vs. 24.1%, p = 0.0074) by European LeukemiaNet 2022 criteria. Overall survival was inferior (11.9 [95% CI, 9.7-15.9] vs. 19.0 months [95% CI, 16.1-23.0], p = 0.0174). At relapse, 30.4% lost and 19.0% gained CD7, suggesting moderate instability over time.

Tagraxofusp, a first-in-class CD123-targeted agent: Five-year postapproval comprehensive review of the literature.

Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.

Hypertensive Emergency with Thrombotic Microangiopathy or TTP? A Case Series and Literature Review.

Thrombotic microangiopathy (TMA) is associated with both hypertensive emergency and primary thrombocytopenia purpura (TTP). However, their clinical management is vastly different, with the latter necessitating urgent plasma exchange (PEX). We report two cases of hypertension-associated TMA (HTN-TMA) and a literature review of the clinical management of malignant hypertension. We suggest that in patients presenting with hypertensive emergency associated with TMA, a clinical diagnosis of HTN-TMA should be made, with emergent treatment to lower blood pressure started immediately. Although TTP is a differential diagnosis for TMA, PEX should not be started concurrently in the absence of other supporting evidence for TTP.

Mechanism of DNA unwinding by MCM8-9 in complex with HROB.

HROB promotes the MCM8-9 helicase in DNA damage response. To understand how HROB activates MCM8-9, we defined their interaction interface. We showed that HROB makes important yet transient contacts with both MCM8 and MCM9, and binds the MCM8-9 heterodimer with the highest affinity. MCM8-9-HROB prefer branched DNA structures, and display low DNA unwinding processivity. MCM8-9 unwinds DNA as a hexamer that assembles from dimers on DNA in the presence of ATP. The hexamer involves two repeating protein-protein interfaces between the alternating MCM8 and MCM9 subunits. One of these interfaces is quite stable and forms an obligate heterodimer across which HROB binds. The other interface is labile and mediates hexamer assembly, independently of HROB. The ATPase site formed at the labile interface contributes disproportionally more to DNA unwinding than that at the stable interface. Here, we show that HROB promotes DNA unwinding downstream of MCM8-9 loading and ring formation on ssDNA.

Adult-specific collagen COL-19 is dispensable for contact-mediated mate recognition in Caenorhabditis elegans.

Mate recognition in C. elegans involves the integration of multiple sensory cues to facilitate the identification of suitable mates for reproductive behaviors. The cuticle, serving as the protective outer layer enveloping the entire body, has been implicated in eliciting contact responses essential for contact-mediated mate recognition in males. However, the specific constituents of cuticular cues have yet to be identified. In this study, we investigate the potential modulatory role of adult-specific collagen COL-19 in contact-mediated mate recognition. Our study shows that the expression of COL-19 ::GFP is adult-specific and not sexually dimorphic. Knockdown of col-19 via RNAi does not affect mate attractiveness of hermaphrodites in male retention assay, as corroborated by generating two independent col-19 putative null mutants via CRISPR/Cas9. These findings suggest that col-19 does not contribute to contact-mediated mate recognition, thereby advancing our mechanistic understanding of the intricate social interactions between sexes in C. elegans .

SOHO State of the Art Updates and Next Questions | Novel Agents and the Diminishing Role of Allogeneic Stem Cell Transplant in B-Acute Lymphoblastic Leukemia.

Outcomes of patients with B-acute lymphoblastic leukemia (B-ALL) have improved remarkably in the past decade. This has largely been due to the development and introduction of novel immunotherapies such as blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T (CAR-T) cells, highly potent tyrosine kinase inhibitors, and improved risk stratification, including better understanding of high risk genomic subgroups and better methods of measurable residual disease (MRD) detection. Historically, allogeneic stem cell transplant (allo-SCT) has been the consolidative treatment of choice in first complete remission for fit adults with B-ALL. However, allo-SCT is associated with significant treatment-related mortality and morbidity. Current research is directed at the incorporation of novel immunotherapies into frontline regimens to improve depth and durability of responses and ultimately increase cure rates. In this review, we will discuss the emerging role of novel immune-based treated strategies in both the frontline and relapsed/refractory settings. We present our approach to newly diagnosed patients with B-ALL and illustrate how the incorporation of novel agents and use of high-sensitivity MRD assays can abrogate the need for allo-SCT in most patients with B-ALL.

Impacts of COVID-19 pandemic on the collection and use of blood and blood components in Taiwan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the supply and transfusion of blood components. This study aims to evaluate changes in blood collection and transfusions during the period following the nationwide Level 3 alert (May-July 2021). METHODS: We retrieved usage data for red blood cells (RBC) from the Taiwan National Health Insurance (NHI) database 2019-2021. RESULTS: During the Level 3 alert period, approximately 85% of COVID-19 cases (11,455/13,624) were in Taipei. In Taipei, blood collection declined by 26.34% and RBC transfusions decreased by 17.14% compared to pre-pandemic levels. RBC usage decreased across all service types, with a significant decrease observed in hematology/oncology by 15.62% (-483 patients, -2,425 units). In non-Taipei regions, blood collection declined by 12.54%, rebounding around one month earlier than in Taipei. The decline in RBC transfusions occurred one month later than in Taipei, with a much lower magnitude (4.57%). Strain on the blood supply occurred in May and June in both Taipei and non-Taipei regions. Among 7,532 hospitalized COVID-19 patients, approximately 6.9% patients required a total of 1,873 RBC transfusions. The rapid increase in COVID-19 inpatients did not significantly increase the burden of blood demands. SUMMARY: During the Level 3 alert, the most significant decline in both RBC collection and transfusions was observed in Taipei. In non-Taipei regions, the decrease in RBC use was only marginal. Notably, there was a significant decrease in RBC use in hematology/oncology in Taipei. This study supports transfusion specialists in seeking efficient ways to address similar future challenges.