Search Results (12,421)

Introduction: Chronic lymphocytic leukemia (CLL) is a common adult leukemia often treated with fludarabine, cyclophosphamide, and rituximab (FCR). While effective, FCR can lead to therapy-related myeloid neoplasms (t-MN), including aggressive therapy-related acute myeloid leukemia (t-AML). Stem cell transplantation offers the best chance for long-term remission in these cases. Here, we report a rare case of t-AML with plasmacytoid dendritic cells (pDC-AML) developing after FCR treatment for CLL that was successfully treated with haplotransplantation. Case Presentation: A 57-year-old woman with CLL-B was treated with six cycles of FCR, achieving a complete response. Six years later, at age 63, she developed t-AML with a rare morphophenotypic subtype: acute myelomonocytic leukemia with plasmacytoid dendritic cells (pDC-AML) and monosomy 8. Diagnostic challenges included distinguishing this subtype from blastic plasmacytoid dendritic cell neoplasm (BPDCN). She was treated with high-dose cytarabine followed by haploidentical stem cell transplantation from her son. Haploidentical transplantation was prioritized due to the urgent clinical need in a patient with high-risk acute leukemia (therapy-related leukemia secondary to prior chemoimmunotherapy and failure to achieve complete remission following the standard 3 + 7 induction protocol). In this critical setting, the patient’s son was immediately available as an HLA-haploidentical donor. Prior to the performance of the haploidentical stem cell transplant from her son, no HLA-matched unrelated donor (MUD) could be identified. Another viable alternative would have been the utilization of umbilical cord blood-derived stem cells harvested from the patient’s twin granddaughters. She was closely monitored post-transplant for potential complications, including graft-versus-host disease (GVHD), post-transplant lymphoproliferative disorder, and thyroid dysfunction, all of which were ruled out during follow-up. The patient remains in complete remission 15 years after her initial CLL diagnosis and 8 years after the t-AML diagnosis and haplotransplantation. Notably, no residual CLL clone was detected at the time of t-AML development, and a benign polyclonal lymphocytosis observed between 2018 and 2020 spontaneously resolved without intervention. Conclusions: This case illustrates the potential for long-term survival in high-risk patients with therapy-related AML developed after cytotoxic treatment for lymphoid malignancies. Haplotransplantation from a semi-identical Human Leukocyte Antigen (HLA) donor proved to be a viable and effective treatment option despite the patient’s age and dual hematologic malignancies. Full article

Background: Dendritic and histiocytic cell sarcoma (DHCS) and clear cell sarcoma (CCS) are ultra-rare soft-tissue sarcomas characterized by diagnostic ambiguity, limited treatment guidelines, and poor outcomes. Their rarity has restricted the development of evidence-based management strategies, leaving clinical decisions reliant on small case series and institutional experience. DHCS typically presents without a unifying molecular driver and is often misclassified without comprehensive immunophenotyping. CCS is defined by EWSR1-ATF1/CREB1 fusions but exhibits low responsiveness to conventional chemotherapy. There remains a clear need to clarify natural history, therapeutic responses, and molecular characteristics in both. Methods: We conducted a retrospective cohort study of adult patients with histologically confirmed DHCS or CCS seen at The Ohio State University Comprehensive Cancer Center between 2010 and 2022. Demographics, treatment modalities, clinical outcomes, and molecular profiles were extracted and analyzed descriptively. Time to progression (TTP) and progression rates by treatment modality were recorded. A structured literature review was conducted to provide context for the findings. Results: Outcomes are descriptive and cohort-specific, reflecting institutional experience rather than generalizable estimates. Total of 10 patients with DHCS and 5 with CCS were evaluable. Most DHCS patients presented with metastatic disease. Among DHCS patients who received systemic therapies, five of eight (62.5%) experienced progression during or shortly after treatment. Among CCS patients who received systemic therapies, three of four (75%) progressed during or shortly after treatment. Overall mortality occurred in 4 of 10 DHCS patients (40%) and 3 of 5 CCS patients (60%). TP53 mutations were identified in four of seven next-generation sequencing (NGS)-tested DHCS cases, and PD-L1 positivity was detected in five of seven tested DHCS cases and one of five tested CCS cases. Conclusions: Despite multimodal treatment, this referral-based cohort of patients with ultra-rare DHCS and CCS showed high rates of progression and mortality. Our findings underscore the urgent need for multi-institutional collaboration and biomarker-driven clinical trials to guide management of these ultra-rare sarcoma subtypes. Full article

Renal fibrosis (RF) represents a major pathological outcome of chronic kidney disease, currently accompanied by extremely limited therapeutic strategies. To decipher key cellular and molecular drivers, we integrated single-cell and bulk transcriptomic profiles for comprehensive analysis. Based on the RF-related single-cell and bulk transcriptomic data, key cell subtypes were identified through Scissor analysis, custom signature matrix construction via CIBERSORTx, and Weighted Gene Co-Expression Network Analysis (WGCNA). Subsequently, key subtype-related biomarkers were identified through the expression analysis, and functional enrichment analysis for biomarkers was conducted to elucidate the potential mechanisms by which biomarkers regulate RF. Through comprehensive profiling, thick ascending limb (TAL) cells were predominant and displayed marked heterogeneity in renal fibrosis (RF), with cortical TAL (CTAL) and adaptive TAL (aTAL) identified as principal subtypes. A set of candidate biomarkers was identified. Quantitative polymerase chain reaction (qPCR) validation in mouse models confirmed aberrant expression of these biomarkers, with STAT1 and PARP8 upregulated and HS6ST2, PTGER3, and TMEM207 downregulated in RF. Furthermore, functional enrichment analyses indicated that these biomarkers were associated with pathways underlying metabolic reprogramming and immune perturbation. Our study implicates CTAL and aTAL as central cellular players in RF and identifies their associated biomarkers. These experimentally validated biomarkers provide novel targets and repurposing opportunities for RF therapeutic intervention. Full article

Background/Objectives: Radiotherapy de-escalation is an established strategy in the management of early breast cancer, supported by randomized evidence predominantly derived from older patient populations. Younger women remain underrepresented in de-escalation trials, despite exhibiting less favorable clinicopathological characteristics associated with increased locoregional recurrence and inferior survival. The objective of this systematic review is to assess the available evidence regarding the safety and implementation of radiotherapy de-escalation strategies in younger patients with early breast cancer. Methods: A literature search following the PRISMA 2020 guidelines was performed to identify studies evaluating radiotherapy de-escalation strategies in younger breast cancer patients. Ongoing and recently completed trials were identified through ClinicalTrials.gov. Epidemiological data, randomized trials, and current clinical guidelines were reviewed. Results: Younger age at diagnosis is consistently associated with more aggressive tumor biology, higher rates of nodal involvement, unfavorable molecular subtypes, and worse survival outcomes. Among de-escalation approaches, moderate hypofractionation (15–16 fractions) is supported by randomized evidence and contemporary guidelines and can be applied irrespective of age. In contrast, evidence supporting ultra-hypofractionation, partial breast irradiation, and omission of radiotherapy in younger patients remains less robust, as these strategies have largely been evaluated in older or postmenopausal populations. Conclusions: Radiotherapy de-escalation in younger patients with breast cancer should be approached with caution. While moderate hypofractionation appears safe regardless of age, more aggressive de-escalation strategies lack adequate evidence in women under 50 years, particularly those under 40. Further prospective studies with sufficient representation of younger patients are required to clarify the role of radiotherapy de-escalation in this population. Full article

Purpose: The aim of this narrative review is to update current knowledge on Moyamoya vasculopathy (MMV) by addressing key diagnostic debates—including laterality; genetic subtypes; regional epidemiology; and features distinguishing Moyamoya Disease (MMD), Moyamoya Syndrome (MMS) and their mimics. Methods: Key and representative studies were identified through PubMed/MEDLINE and Scopus, focusing on publications from 2014–2025 while also considering earlier seminal works. Results: MMD typically presents with bilateral steno-occlusion of the terminal internal carotid arteries (ICAs) and proximal middle and anterior cerebral arteries (MCAs/ACAs) due to concentric vascular thickening, accompanied by characteristic ‘puff-of-smoke’ collaterals, whereas MMS shows a similar but more often unilateral pattern with fewer collaterals, influenced by the underlying condition. However, this distinction often fails to reflect the full clinical and radiological variability of the Moyamoya spectrum. Atypical moyamoya-like patterns, often confined to M1 or A1 segments, further complicate diagnosis. Clinical manifestations ranged from asymptomatic cases to ischemic or hemorrhagic strokes, and occasionally seizures. Diagnosis relied on multimodal imaging (DSA, MRA, CTA), but genetic mutations, contributing to radiological variability, often complicate differentiation between MMD, MMS, and mimics. Management is pattern-specific: MMS and atypical forms are generally managed conservatively, whereas MMD frequently requires surgical revascularization, particularly in children and symptomatic adults. Nevertheless, variability within diagnostic categories limits the applicability of rigid treatment protocols. Conclusions: Current diagnostic algorithms remain limited. Integrating advanced imaging findings with clinical, genetic, and epidemiological data is essential to define the full disease spectrum, improve diagnostic accuracy, and inform patient management and outcome assessment. Full article

Background: Fulminant type 1 diabetes (FT1D) is a rare but life-threatening subtype of type 1 diabetes. The concurrence of FT1D with myocarditis is uncommon and attracts further clinical attention. Case Presentation: A 33-year-old female was transferred by a local hospital to West China Hospital because of altered consciousness, abrupt onset of hyperglycemia with ketoacidosis, significantly increased cardiac biomarkers, and ST segment elevations. Her random blood glucose at the local hospital was 50.19 mmol/L. Insulin infusion and fluid resuscitation were started immediately before referral. On admission, her random blood glucose was 14.17 mmol/L. HbA1C and glycosylated albumin (GA) were 6.3% and 21.45%, respectively. Her fasting C-peptide level was 0.022 nmol/L. Anti-Glutamic Acid Decarboxylase (anti-GAD) antibody was 25.06 IU/mL. FT1D was diagnosed based on the 2012 New Diagnosis Criteria of FT1D. Electrocardiogram showed significant ST segment elevation in leads II, III, aVF, and V3-V6. Echocardiography revealed a mildly reduced left ventricular ejection fraction (LVEF) of 46%. Coronary angiography displayed no abnormality. Cardiac magnetic resonance imaging revealed areas of increased signal intensity in the interventricular septum, basal and mid inferolateral walls, and apical inferior wall and subepicardial late gadolinium enhancement (LGE), particularly in the lateral aspects of the left ventricle on T2-weighted imaging (T2WI). Acute myocarditis was diagnosed based on the European Society of Cardiology 2013 Task Force Criteria. She was treated with insulin, fluid resuscitation, and supportive care, leading to rapid recovery of ketoacidosis and cardiac function. At the four-month follow-up, she remained on insulin therapy with good glycemic control but persistent low C-peptide levels. Conclusion: This case report raises awareness about FT1D, determines the differential diagnosis of acute cardiac presentations in an FT1D patient, and highlights clinical reasoning so that clinicians can recognize and manage similar presentations on time. Full article

Menin inhibitors are the first targeted therapies for KMT2A-rearranged and NPM1-mutated acute leukemias, addressing a significant unmet need in these high-risk subtypes. Revumenib received approval in 2024–2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML. The AUG-MENT-101 trial reported a 23% composite complete remission rate in heavily pretreated patients, with 61% of responders achieving MRD negativity. Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development. They demonstrate similar efficacy, but their safety profiles differ, especially regarding QTc prolongation and coverage of resistance mutations. Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment. Acquired resistance, often due to MEN1 mutations at the drug-binding interface, occurs in about 40% of cases. Distinct resistance patterns among menin inhibitors suggest the possibility of sequential therapy. Approximately 30–40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination. Full article

Background: In advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS). However, clinical outcomes vary according to EGFR mutation subtype and TP53 co-mutations. Most prior studies have evaluated TP53 status as binary, and the clinical relevance of domain-specific TP53 alterations remains insufficiently defined. Methods: We retrospectively analyzed patients with advanced NSCLC harboring sensitizing EGFR mutations who received first-line EGFR-TKI therapy at the National Cancer Centre Singapore between 22 November 2007, and 17 February 2022. EGFR mutations were classified as common (exon 19 deletion or L858R) or uncommon (all others). TP53 alterations were categorized into three groups: (i) DNA-binding domain (DBD)-involved mutations, including DBD-only mutations and those with additional oligomerization domain (OD) involvement; (ii) other TP53 mutations not involving the DBD or OD; and (iii) TP53 wild type (TP53-WT). The primary endpoint was PFS. Survival analyses were performed using the Kaplan–Meier method and Cox proportional hazards models. Results: TP53 alterations were identified in approximately half of the cohort and were predominantly concentrated within the DBD. In the overall cohort, patients treated with third-generation EGFR-TKIs had longer PFS than those treated with first- or second-generation EGFR-TKIs, with this difference being more pronounced among patients with TP53-mutant tumors; no clear PFS difference by TKI generation was observed in the TP53-WT subgroup. Patients with common EGFR mutations experienced significantly longer PFS than those with uncommon mutations, particularly in the presence of TP53 co-mutations. Across multiple analyses, TP53 DBD-involved mutations were associated with shorter PFS compared with other TP53 mutations and TP53-WT, especially in patients treated with first- or second-generation EGFR-TKIs and in those with common EGFR mutations. Conclusions: In EGFR-mutant NSCLC treated with EGFR-TKIs, TP53 functional domain involvement provides prognostic information beyond TP53 mutation status alone. TP53 DBD-involved alterations define a high-risk subgroup with inferior PFS, particularly in treatment settings using first- or second-generation EGFR-TKIs. Incorporation of TP53 domain-based classification, together with EGFR mutation subtype, may improve risk stratification and help guide treatment planning in EGFR-mutant NSCLC. Full article

Metallothioneins (MTs) and heat shock protein 70 (HSP70) are key regulators of cellular stress response and metal homeostasis and play important roles in tumor biology. The aim of this study was to examine their expression patterns and potential prognostic significance in different molecular subtypes of breast cancer (BC), with special emphasis on triple-negative breast cancer (TNBC) and the Luminal A subtype, compared with benign breast lesions (fibroadenomas). A total of 90 tissue samples were included, and the expression of MTs in the cytoplasm and nucleus and HSP70 in the nucleus of tumor cells was analyzed immunohistochemically and correlated with clinicopathological features and treatment outcomes. Distinct expression patterns of HSP70 and MTs were observed between malignant and benign samples, as well as among the analyzed molecular subtypes of BC, suggesting their involvement in cellular adaptive mechanisms associated with malignant transformation. TNBC was characterized by less favorable clinicopathological features compared to the Luminal A subtype, including higher histological grade, increased proliferative activity, and a higher incidence of recurrence and metastatic disease. Survival analyses confirmed a worse outcome for patients with TNBC, while HSP70 and MTs expression did not show independent prognostic value in multivariate models. In conclusion, although HSP70 and MTs play important biological roles in the cellular response to stress and tumor adaptation, their expression in this study does not represent an independent prognostic indicator of clinical outcome. Nevertheless, the observed expression patterns provide insight into the complex mechanisms of tumor adaptation and emphasize the need for integrative approaches in BC biomarker research. Full article

Understanding the circulation of influenza A viruses and other respiratory pathogens in Antarctic wildlife is essential for anticipating outbreaks and evaluating potential impacts on vulnerable populations. During the austral summer of December 2024 and January 2025, we conducted viral surveillance in six bird species breeding at Lions Rump, King George Island, South Shetland Islands, Antarctica. A total of 199 individuals were sampled, including Pygoscelis papua (gentoo penguin; n = 81), Pygoscelis adeliae (Adélie penguin; n = 79), Pygoscelis antarcticus (chinstrap penguin; n = 34), Stercorarius antarcticus (brown skua; n = 2), Chionis albus (snowy sheathbill; n = 2), and Eudyptes chrysolophus (macaroni penguin; n = 1). All cloacal and oropharyngeal swabs tested negative for influenza A viruses and coronaviruses by RT-PCR. Blood samples from 177 birds were screened by enzyme-linked immunosorbent assay, which detected influenza A virus antibodies in 20 individuals (11.3%). Hemagglutination inhibition assays identified subtypes H6 and H11 in two penguins and H1, H5, H6, and H9 in one skua. These findings reveal no evidence of active viral infection during the sampling period but provide serological evidence of past exposure in seabird populations at Lions Rump. Continued surveillance is essential to characterize viral dynamics in Antarctic ecosystems and to support early detection and preparedness for potential incursions of emerging high-pathogenicity influenza A viruses. Full article

In the post-pandemic era, student mental health challenges have emerged as a critical issue in higher education. However, conventional assessment approaches often treat at-risk populations as a monolithic entity, thereby limiting intervention effectiveness. This study proposes a novel computational framework that integrates explainable artificial intelligence (XAI) with unsupervised learning to decode the latent heterogeneity of psychological risk mechanisms. We developed a “predict-explain-discover” pipeline leveraging TreeSHAP and Gaussian Mixture Models to identify distinct risk subtypes based on a 2556-dimensional feature space encompassing lexical, linguistic, and affective indicators. Our approach identified three theoretically-grounded subtypes: academically-driven (28.46%), socio-emotional (43.85%), and internal regulatory (27.69%) risks. Sensitivity analysis using top-20 core features further validated the structural stability of these mechanisms, proving that the subtypes are anchored in the model’s primary decision drivers rather than high-dimensional noise. The framework demonstrates how black-box classifiers can be transformed into diagnostic tools, bridging the gap between predictive accuracy and mechanistic understanding. Our findings align with the Research Domain Criteria (RDoC) and establish a foundation for precision interventions targeting specific risk drivers. This work advances computational mental health research through methodological innovations in mechanism-based subtyping and practical strategies for personalized student support. Full article

Breast cancer (BC) is a global health problem. BC is a biologically heterogeneous disease in which novel immunotherapeutic strategies are needed, particularly in the metastatic setting. The NKG2D/NKG2D ligand (NKG2DL) axis is a key component of innate antitumor immunity and represents a potential therapeutic target, but its relevance in BC has not been fully characterized. We performed an in silico analysis of NKG2DL expression in BC cell lines, healthy breast tissue, and tumor samples using publicly available transcriptomic databases (DSMZCellDive, ShinyTHOR, GTEx, TCGA, Human Protein Atlas), complemented by survival analyses from TCGA and KMPlot and a narrative review of the literature. NKG2DL transcripts were consistently expressed in BC cell lines and tumor tissues, with higher expression observed in ductal histology, higher tumor stage, and basal molecular subtype. Survival analyses showed heterogeneous and generally weak associations between individual NKG2DLs and clinical outcomes. In silico proteomics data are scarce, but the narrative review showed that NKG2DLs are expressed by immunohistochemistry in tumor tissues but absent in surrounding healthy tissues. The literature review also revealed concomitant dysfunction of NKG2D+ effector cells due to multiple resistance mechanisms (including ligand shedding). We also review potential therapeutic approaches. Full article

Background/Objectives: Bipolar disorder (BD) is a chronic psychiatric condition characterized by episodes of mania, hypomania, and depression. Due to the cognitive impairments associated with BD, patients frequently experience difficulties in attention, memory, and executive functions, which in turn adversely affect specific aspects of their language abilities, such as word retrieval, verbal fluency, and the organization of coherent speech. The present study aims to determine the extent to which the verbal fluency skills of native Turkish-speaking individuals with BD are impaired compared to healthy controls and to identify whether there are differences in verbal fluency skills and their subcategories between bipolar I disorder (BD I) and bipolar II disorder (BD II) groups. Methods: A cross-sectional comparative design was employed in this study, including 39 euthymic patients diagnosed with BD I or BD II and 39 healthy controls. Verbal fluency was assessed using a standardized task comprising semantic fluency, semantic switching, phonemic fluency, and automatic speech subtests. All assessments were conducted under blinded conditions, and scoring was performed by independent raters. Group comparisons were carried out using ANOVA, Kruskal–Wallis, and ANCOVA analyses; age was controlled for through covariance analysis. Additionally, sensitivity analyses were conducted within the 25–55 age range. Results: The control group demonstrated significantly higher performance than the BD groups across all semantic and phonemic verbal fluency tasks. No statistically significant differences were observed between the groups in automatic speech tasks. When comparing the BD I and BD II groups, a statistically significant difference was found only in the action (verb) category, with the BD II group outperforming the BD I group. Conclusions: The findings indicate that bipolar disorder is associated with marked impairments in semantic and phonemic verbal fluency, while automatic speech abilities appear to be relatively preserved. Moreover, the observed difference between BD subtypes—particularly in the action (verb) category—suggests that the type of the disorder may differentially influence cognitive–linguistic functioning. Full article

Triple-negative breast cancer (TNBC), particularly the androgen receptor-low (AR-low) subtype, is one of the most aggressive and hard-to-treat forms of BC, characterized by a high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel therapy resistance, metastases, and poor clinical outcomes. An integrated framework describing the dysregulated molecular networks that support the pathobiology of AR-low TNBC is lacking. Multiple published studies in breast cancer have previously proposed mechanistic links between TP53 loss, AR-low states, and heightened FOXM1-driven G2/M transcriptional programs, potentially via deregulation of E2F activity, chromatin-associated co-regulators (e.g., ATAD2), and disruption of repressive networks involving p53–p21–DREAM and SPDEF. Additional reports suggest that FOXM1-associated circuitry may be reinforced by chromatin regulators such as WDR5 and by mitotic/spindle factors such as ASPM, including through feedback interactions and condensate-associated transcriptional organization. We previously showed that FOXM1, a master regulator transcription factor, is upregulated and is a biomarker of poor prognosis in AR-low TNBC. In this study, we filtered a set of “TNBC core genes” known to promote transcriptional chaos downstream of FoxM1. We identified a set of 15 cell cycle regulators—including mitotic kinesin motors (KIF14, KIF11, KIF4A, KIF2C, and KIF20A), centromeric proteins (CENPA, CENPO, CENPL, CENPF, and OIP5), and regulators of proteolysis (UBE2C, UBE2S, UBE2T, PSMD14, and TUBA1B). These 15 genes, which were ranked highly among genes overexpressed in TNBC featured prominently in gene signatures of chromosomal instability and were also overexpressed among AR-low TNBCs and TP53-mutant breast tumors. We show that expression of each of these 15 genes correlates positively with proliferation markers (Ki67, PCNA, and MCM2) in TNBC, and that the overexpression of this gene set is associated with shorter relapse-free survival and distinct immune/stromal infiltration patterns. In light of prior work, our findings point to a FOXM1-associated 15-gene signature enriched in AR-low TNBC and associated with the high-proliferation and high-CIN phenotypes of this clinically challenging tumor type. This 15-gene set represents an actionable vulnerability with therapeutic potential for AR-low TNBC and provides a framework for rethinking how to manage highly proliferative, genomically unstable BCs. Full article

Phosphatidylinositol and its derivatives are essential components of cell membranes and play pivotal roles in growth signaling pathways. In the human primordial placenta, phosphatidylinositol synthesis is catalyzed by phosphatidylinositol synthase (PIS) and the phosphatidylinositol-exchange enzyme (IE), both of which require divalent cations. We investigated whether GTP-binding proteins modulate this biosynthetic process. Incorporation of [³H]inositol into phosphatidylinositol was measured in trophoblast tissue and microsomes from 8 to 10-week placentas. Our results demonstrate that Mn²⁺ strongly enhances phosphatidylinositol synthesis, and stimulation with AlF₄⁻ further increases incorporation rates by up to 2.5-fold. In contrast, Mg²⁺ combined with the non-hydrolyzable GTP analog GIDP elevated synthesis by 58%, whereas Mn²⁺ plus GIDP reduced incorporation by 30%. Complementary in silico protein–protein interaction analyses suggest that G-proteins may directly associate with inositol-exchange enzymes, providing a potential mechanism for the observed regulatory effects. These findings indicate that phosphatidylinositol synthesis is modulated in a manner consistent with G-protein involvement, with distinct effects depending on the prevailing enzymatic pathway. We propose that rapid trophoblast proliferation may involve feedback mechanisms mediated by distinct G-protein subtypes acting on early steps of the phosphatidylinositol cycle. Full article