A rare case of Philadelphia-positive (P210BCR-ABL1) T-cell acute lymphoblastic leukemia/lymphoma associated with minimal residual disease persistence after intensive chemotherapeutic approaches.

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a rare and aggressive leukemia. Philadelphia chromosome-positive cytogenetic abnormality is most common in CML. It is difficult to differentiate between de novo Ph+ T-ALL/LBL and T-cell lymphoblastic crises of CML. We present a case of adult Ph+ T-ALL/LBL with a likely history of antecedent CML. Initially thought to be a case of chronic-phase CML, a diagnostic quandary led to the pursuit of a lymph node biopsy that established the diagnosis of Ph+ T-LBL or T lymphoblastic blast crisis of CML, a clinical presentation extremely rare and only the second of its kind from our review of the literature. The patient was treated with an intensive chemotherapy regimen for over a year due to persistent minimal residual disease (MRD) positivity indicating aggressive disease.

Isolation and Detection of Pathological Tau Species in a Tauopathy Mouse Model.

Tau protein in Alzheimer's disease (AD) and tauopathies becomes insoluble due to hyperphosphorylation, conformational alterations, and aggregation. To analyze insoluble tau and pathological tau species, this study employs a methodology that utilizes wild-type and transgenic tau mice (P310S Tau) tissue extraction using 1% Sarkosyl or N-Lauroylsarcosine sodium salt and the radio immunoprecipitation assay (RIPA) buffer. However, the commonly used methods to study the insoluble tau fraction using detergents like Sarkosyl and RIPA require a large amount of homogenate, which can pose challenges when dealing with small tissue samples. Additionally, the study employs immunohistochemistry to visualize and quantify the pathological tau species in the brain tissue of transgenic mice, aiming to identify and analyze pathological tau species such as hyperphosphorylated tau to further our understanding of tauopathies such as Alzheimer's disease.

Efficacy and safety of mitoxantrone, etoposide, and cytarabine for treatment of relapsed or refractory acute myeloid leukemia.

BACKGROUND/RATIONALE: Most patients with acute myeloid leukemia (AML) develop relapsed or refractory (R/R) disease after receiving initial induction chemotherapy. Salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative therapy for R/R AML. Mitoxantrone, etoposide, and cytarabine (MEC) is the current standard of care salvage regimen for R/R AML at Cleveland Clinic. The primary objective was to determine the overall remission rate (ORR: defined as patients achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)) in R/R AML patients who received MEC. METHODS: Adult patients with R/R AML treated with MEC between July 1, 2014 and September 30, 2022 were included. ORR and its association with baseline characteristics were determined. Secondary outcomes included overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), and safety. RESULTS: Sixty patients were evaluated. The ORR was 51.7% (33.3% CR and 18.3% CRi). The median time from receipt of MEC to CR/CRi was 7.7 weeks. Patients with bone marrow blasts ≤20% and peripheral blood blasts ≤30% at MEC initiation were more than twice as likely to achieve CR/CRi compared to those with a higher blast burden. The median OS was 6.3 months. Twenty-four (40.0%) patients proceeded to alloHSCT. Twenty-one (35.0%) patients were transferred to the intensive care unit (ICU) during their admission. CONCLUSIONS: MEC is an effective salvage regimen for patients with R/R AML, especially among those with low disease burden at initiation. Febrile neutropenia, infections, and severe oral mucositis were common with MEC administration.

Heavy metal geochemistry and toxicity assessment of water environment from Ib valley coalfield, India: Implications to contaminant source apportionment and human health risks.

The present study aims to investigate the hydrogeochemical evolution of heavy metals and assesses impacts of mining activities on the groundwater resources and potential human health risks in the coal mining areas of Ib valley coalfield. In this perspective, a total of one hundred and two mine water and groundwater samples were collected from different locations. The water samples were analysed for some selected heavy metals i.e. Mn, Cu, Pb, Zn, Ni, Co, As, Se, Al, Sr, Ba, Cd, Cr, V and Fe using ICP-MS. In addition, pH and SO42- concentration were also measured following APHA procedure. The water pH in the Ib valley coalfields ranged from 3.26 to 8.18 for mine water and 5.23 to 8.52 for groundwater, indicating acidic to alkaline nature of water. Mn in mine water and Zn in groundwater environment were observed as the most dominant metals. The water hazard index (WHI) reflects that around 80% of mine water are non-toxic (WHI<5), 5% slightly toxic (510) and 15% extremely toxic (WHI>15). Relatively high pH and low concentration of dissolved metals and SO42- in groundwater as compared to mine water indicate lesser impact of mining activities. The calculated drinking water quality index (DWQI) suggests that Mn, Al, Ni and Fe in mine water and Mn, Fe, Ni and Pb in groundwater were the major objectionable metals which caused the water quality deterioration for drinking uses. Further, the non-carcinogenic health risk assessment for adult male, female and child populations identifies Co, Mn, Ni as the key elements making the water hazardous for human health. Comparatively higher ratio of ingestion rate and body weight in child population might be causing higher health risks in child population as compared to adult male and adult female population.

Role of Single Port Rigid Thoracoscopy in Undiagnosed Pleural Effusion.

BACKGROUND: In recent years, medical thoracoscopy has been well established to play an important role in undiagnosed pleural effusion; however, this procedure is underutilized due to limited availability of the instruments it requires. This study analysed the outcome of single port rigid thoracoscopy in patients with undiagnosed pleural effusions. METHODS: This study retrospectively analysed the outcomes of all patients with undiagnosed pleural effusion presenting to our centre between 2016 to 2020 who underwent single port rigid medical thoracoscopy as a diagnostic procedure. RESULTS: In total, 92 patients underwent single port rigid medical thoracoscopy. The most common presenting symptom was shortness of breath. A majority of the patients had lymphocytic exudative pleural effusion. The average biopsy sample size was 18 mm, and no major complication was reported in any of the patients. CONCLUSION: Single port rigid thoracoscopy is a safe and well-tolerated procedure that yields a biopsy of a larger size with high diagnostic yield. Moreover, the low cost of the instruments required by this procedure makes it particularly suited for use in developing countries.

The crossroads of cancer therapies and clonal hematopoiesis.

The intricate interplay between Clonal Hematopoiesis (CH) and the repercussions of cancer therapies has garnered significant research focus in recent years. Previously perceived as an age-related phenomenon, CH is now closely linked to inflammation ("Inflammaging") and cancer, impacting leukemogenesis, cancer progression, and treatment responses. This review explores the complex interplay between CH and diverse cancer therapies, including chemotherapy, targeted treatments, radiation, stem cell transplants, CAR-T cell therapy, and immunotherapy, like immune checkpoint inhibitors. Notably, knowledge about post-chemotherapy CH mutation/acquisition has evolved from a de novo incident to more of a clonal selection process. Chemotherapy and radiation exposure, whether therapeutic or environmental, increases CH risk, particularly in genes like TP53 and PPM1D. Environmental toxins, especially in high-risk environments like post-disaster sites or space exploration, are associated with CH. CH affects clinical outcomes in stem cell transplant scenarios, including engraftment, survival, and t-MN development. The presence of CH also alters CAR-T cell therapy responses and impacts the efficacy and toxicity of immunotherapies. Furthermore, specific mutations like DNMT3A and TET2 thrive under inflammatory stress, influencing therapy outcomes and justifying the ongoing tailored interventions in clinical trials. This review underscores the critical need to integrate CH analysis into personalized medicine, enhancing risk assessments and refining treatment strategies. As we progress, multidisciplinary collaboration and comprehensive studies are imperative. Understanding CH's impact, especially concerning genotoxic stressors, will inform screening, surveillance, and early detection strategies, decreasing the risk of therapy-related myeloid neoplasms and revolutionizing cancer treatment paradigms.

Development of a [89Zr]Zr-labeled Human Antibody using a Novel Phage-displayed Human scFv Library.

PURPOSE: Tax-interacting protein 1 (TIP1) is a cancer-specific radiation-inducible cell surface antigen that plays a role in cancer progression and resistance to therapy. This study aimed to develop a novel anti-TIP1 human antibody for noninvasive PET imaging in patients with cancer. EXPERIMENTAL DESIGN: A phage-displayed single-chain variable fragment (scFv) library was created from healthy donors' blood. High-affinity anti-TIP1 scFvs were selected from the library and engineered to human IgG1. Purified Abs were characterized by size exclusion chromatography high-performance liquid chromatography (SEC-HPLC), native mass spectrometry (native MS), ELISA, BIAcore, and flow cytometry. The labeling of positron emitter [89Zr]Zr to the lead Ab, L111, was optimized using deferoxamine (DFO) chelator. The stability of [89Zr]Zr-DFO-L111 was assessed in human serum. Small animal PET studies were performed in lung cancer tumor models (A549 and H460). RESULTS: We obtained 95% pure L111 by SEC-HPLC. Native MS confirmed the intact mass and glycosylation pattern of L111. Conjugation of three molar equivalents of DFO led to the optimal DFO-to-L111 ratio of 1.05. Radiochemical purity of 99.9% and specific activity of 0.37 MBq/µg was obtained for [89Zr]Zr-DFO-L111. [89Zr]Zr-DFO-L111 was stable in human serum over 7 days. The immunoreactive fraction in cell surface binding studies was 96%. In PET, preinjection with 4 mg/kg cold L111 before [89Zr]Zr-DFO-L111 (7.4 MBq; 20 µg) significantly (P < 0.01) enhanced the tumor-to-muscle standard uptake values (SUVmax) ratios on day 5 compared with day 2 postinjection. CONCLUSIONS: L111 Ab targets lung cancer cells in vitro and in vivo. [89Zr]Zr-DFO-L111 is a human antibody that will be evaluated in the first in-human study of safety and PET imaging.

Snow Cover Response to Climatological Factors at the Beas River Basin of W. Himalayas from MODIS and ERA5 Datasets.

Glaciers and snow are critical components of the hydrological cycle in the Himalayan region, and they play a vital role in river runoff. Therefore, it is crucial to monitor the glaciers and snow cover on a spatiotemporal basis to better understand the changes in their dynamics and their impact on river runoff. A significant amount of data is necessary to comprehend the dynamics of snow. Yet, the absence of weather stations in inaccessible locations and high elevation present multiple challenges for researchers through field surveys. However, the advancements made in remote sensing have become an effective tool for studying snow. In this article, the snow cover area (SCA) was analysed over the Beas River basin, Western Himalayas for the period 2003 to 2018. Moreover, its sensitivity towards temperature and precipitation was also analysed. To perform the analysis, two datasets, i.e., MODIS-based MOYDGL06 products for SCA estimation and the European Centre for Medium-Range Weather Forecasts (ECMWF) Atmospheric Reanalysis of the Global Climate (ERA5) for climate data were utilized. Results showed an average SCA of ~56% of its total area, with the highest annual SCA recorded in 2014 at ~61.84%. Conversely, the lowest annual SCA occurred in 2016, reaching ~49.2%. Notably, fluctuations in SCA are highly influenced by temperature, as evidenced by the strong connection between annual and seasonal SCA and temperature. The present study findings can have significant applications in fields such as water resource management, climate studies, and disaster management.

Suprascapular Nerve Block (SSNB) improves the outcome in exercise based management of Primary Adhesive Capsulitis (PAC): A prospective randomized comparative study.

Background and Aims: Increased pain and associated stiffness hinders the advantages of exercise and process of recovery in primary adhesive capsulitis. We hypothesized that suprascapular nerve block may positively affect the outcome due to its role in pain relief of acute or chronic shoulder pain. We compared the effect of suprascapular nerve block and exercise with only exercise on the recovery of primary adhesive capsulitis. Material and Methods: A total of 96 patients of both sexes presenting with primary adhesive capsulitis were divided by computer randomization in two equal groups (n = 48). Group A received exercise only and Group B received suprascapular nerve block followed by exercise. Oral paracetamol was given for analgesia as desired. Patients were followed up at 4, 8, 16, and 24 weeks. Pain was assessed by visual analog scale; functional outcome by Shoulder Pain and Disability Index and range of movement by goniometer. Results: The pain scores and Shoulder Pain and Disability Index scores were significantly lower at all observation points of 4, 8,16, and 24 weeks in Group B than Group A (P < 0.05). The range of movement in all the ranges of forward flexion, extension, internal and external rotation, and abduction at all observation points was significantly higher in Group-B (P < 0.05) compared to Group A. The consumption of analgesics was significantly more in Group A than Group B at 4 and 8 weeks (P = 0.020 and P = 0.044) but comparable at 12 and 24 weeks (P = 0.145 and P = 0.237 respectively). Conclusion: Combining SSNB with exercise is more effective in treatment of primary adhesive capsulitis than exercise alone and reduces the use of analgesics. SSNB it is effective and safe to use in primary adhesive capsulitis.

Association of Umbilical Cord Coiling and Medical Disorders of Pregnancy: a Cross-Sectional Study.

Introduction: The coiling of the umbilical vessels develops by about 28 days post-conception and is present in about 95% of foetuses by around nine weeks of conception. Umbilical coiling (UC) is associated with many maternal and fetal outcomes. The present study attempts to assess any associations between medical disorders of pregnancy with umbilical cord coiling. Methodology: This cross-sectional study was conducted in the Department of Obstetrics and Gynaecology, Gandhi Medical College δ Sultania Zanana Hospital, Bhopal, India, from January to December 2020. A total of 300 obstetric mothers were included in the study. Coiling of the umbilical cord numbers and pattern and umbilical coiling index was assessed at the time of delivery. Medical disorders such as diabetes mellitus, hypertension and thyroid disorders during pregnancy were evaluated at the time of delivery. Data was entered and analysed with Epi info software. Results:Gestational diabetes mellitus was seen in hyper-coiled and normocoiled, but not also in hypocoiled UC. Hypothyroidism with GDM was seen only in hypocoiled UC. A significant association was seen with selected endocrinal medical problems with umbilical cord coiling (P value <0.05). The most common blood pressure-related disorder identified in the present study is eclampsia (66.66%). Gestational hypertension was seen only in hypocoiled UC coiling. Conclusion:The most common endocrine disorder associated with umbilical cord coiling was gestational diabetes in hyper coiled and normocoiled UC. Hypocoiling and normocoiling have been found in medical disorders of pregnancy. Multicentric studies are required to identify the relationship between endocrine and blood pressure-related disorders and umbilical coiling.

π-Stacking among the Anthracenyl Groups of a Copper Complex Resulted in Doubling of Unit Cell Volume To Provide New Polymorphs.

Two polymorphs of the 9-N-(3-imidazolylpropylamino)methylanthracene (Hanthraimmida) containing hydrated copper(II)-2,6-pyridinedicarboxylate complex are reported. The two polymorphs have either lamellar or Herringbone arrangements of π-stacks among the anthracenyl groups of organocation. The difference between the two polymorphs originated from having face-to-face stacking arrangements between the two anthracenyl groups of the symmetry independent cations within the unit cell in one of the polymorphs. The π-stacked anthracenyl groups in consecutive layers of the polymorphs are oriented in one direction in the polymorph designated as P1, whereas the polymorph designated as P2 has such orientations in opposite directions. The unit cell volume of the polymorph P2 (Z = 4) has approximately twice the volume of the polymorph P1 (Z = 2); it happend due to coalescence of two unit cells of P1 in the ab-crystallographic plane. A mixed methanol/water solvate of the copper complex is also reported. It has a channel-like arrangement of the cations; has the anions and the solvents within the cation embraced channel-like enclosures. This complex is unstable, once taken out from the methanol solvent, it transforms in real time to P2 by replacements of the methanol molecules by water molecules.

Blocking the functional domain of TIP1 by antibodies sensitizes cancer to radiation therapy.

Non-small-cell lung cancer (NSCLC) and glioblastoma (GB) have poor prognoses. Discovery of new molecular targets is needed to improve therapy. Tax interacting protein 1 (TIP1), which plays a role in cancer progression, is overexpressed and radiation-inducible in NSCLC and GB. We evaluated the effect of an anti-TIP1 antibody alone and in combination with ionizing radiation (XRT) on NSCLC and GB in vitro and in vivo. NSCLC and GB cells were treated with anti-TIP1 antibodies and evaluated for proliferation, colony formation, endocytosis, and cell death. The efficacy of anti-TIP1 antibodies in combination with XRT on tumor growth was measured in mouse models of NSCLC and GB. mRNA sequencing was performed to understand the molecular mechanisms involved in the action of anti-TIP1 antibodies. We found that targeting the functional domain of TIP1 leads to endocytosis of the anti-TIP1 antibody followed by reduced proliferation and increased apoptosis-mediated cell death. Anti-TIP1 antibodies bound specifically (with high affinity) to cancer cells and synergized with XRT to significantly increase cytotoxicity in vitro and reduce tumor growth in mouse models of NSCLC and GB. Importantly, downregulation of cancer survival signaling pathways was found in vitro and in vivo following treatment with anti-TIP1 antibodies. TIP1 is a new therapeutic target for cancer treatment. Antibodies targeting the functional domain of TIP1 exhibited antitumor activity and enhanced the efficacy of radiation both in vitro and in vivo. Anti-TIP1 antibodies interrupt TIP1 function and are effective cancer therapy alone or in combination with XRT in mouse models of human cancer.

Gastrointestinal Manifestations of SARS-CoV-2: Transmission, Pathogenesis, Immunomodulation, Microflora Dysbiosis, and Clinical Implications.

The clinical manifestation of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the respiratory system of humans is widely recognized. There is increasing evidence suggesting that SARS-CoV-2 possesses the capability to invade the gastrointestinal (GI) system, leading to the manifestation of symptoms such as vomiting, diarrhea, abdominal pain, and GI lesions. These symptoms subsequently contribute to the development of gastroenteritis and inflammatory bowel disease (IBD). Nevertheless, the pathophysiological mechanisms linking these GI symptoms to SARS-CoV-2 infection remain unelucidated. During infection, SARS-CoV-2 binds to angiotensin-converting enzyme 2 and other host proteases in the GI tract during the infection, possibly causing GI symptoms by damaging the intestinal barrier and stimulating inflammatory factor production, respectively. The symptoms of COVID-19-induced GI infection and IBD include intestinal inflammation, mucosal hyperpermeability, bacterial overgrowth, dysbiosis, and changes in blood and fecal metabolomics. Deciphering the pathogenesis of COVID-19 and understanding its exacerbation may provide insights into disease prognosis and pave the way for the discovery of potential novel targets for disease prevention or treatment. Besides the usual transmission routes, SARS-CoV-2 can also be transmitted via the feces of an infected person. Hence, it is crucial to implement preventive and control measures in order to mitigate the fecal-to-oral transmission of SARS-CoV-2. Within this context, the identification and diagnosis of GI tract symptoms during these infections assume significance as they facilitate early detection of the disease and the development of targeted therapeutics. The present review discusses the receptors, pathogenesis, and transmission of SARS-CoV-2, with a particular focus on the induction of gut immune responses, the influence of gut microbes, and potential therapeutic targets against COVID-19-induced GI infection and IBD.

Single-Cell Next-Generation Sequencing to Monitor Hematopoietic Stem-Cell Transplantation: Current Applications and Future Perspectives.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are genetically complex and diverse diseases. Such complexity makes challenging the monitoring of response to treatment. Measurable residual disease (MRD) assessment is a powerful tool for monitoring response and guiding therapeutic interventions. This is accomplished through targeted next-generation sequencing (NGS), as well as polymerase chain reaction and multiparameter flow cytometry, to detect genomic aberrations at a previously challenging leukemic cell concentration. A major shortcoming of NGS techniques is the inability to discriminate nonleukemic clonal hematopoiesis. In addition, risk assessment and prognostication become more complicated after hematopoietic stem-cell transplantation (HSCT) due to genotypic drift. To address this, newer sequencing techniques have been developed, leading to more prospective and randomized clinical trials aiming to demonstrate the prognostic utility of single-cell next-generation sequencing in predicting patient outcomes following HSCT. This review discusses the use of single-cell DNA genomics in MRD assessment for AML/MDS, with an emphasis on the HSCT time period, including the challenges with current technologies. We also touch on the potential benefits of single-cell RNA sequencing and analysis of accessible chromatin, which generate high-dimensional data at the cellular resolution for investigational purposes, but not currently used in the clinical setting.

Iron(III) ion-assisted transformation of ZIF-67 to a self-supported FexCo-layered double hydroxide for improved water oxidation.

Herein, we have demonstrated Lewis acid Fe(III)-assisted hydroxylation of ZIF-67 to form FexCo-layered double hydroxide (LDH) nanosheets. The catalyst Fe0.4Co-LDH produced an excellent water oxidation activity to reach a current density of 20 mA cm-2 at only 190 mV overpotential, superior to that of hydrothermally synthesized LDH with a similar composition.

Overview of the Management of Higher-Risk Myelodysplastic Syndromes.

ABSTRACT: Myelodysplastic syndromes or myelodysplastic neoplasms (both abbreviated MDSs) (Leukemia 2022;36:1703-1719) have historically been challenging diseases to treat owing to their complex biology, molecular diversity, and a patient population that is elderly with comorbidities. As the patients are living longer, incidence of MDSs is rising, and challenges in selecting MDS treatments or lack thereof have been becoming more apparent. Fortunately, with better understanding of molecular underpinnings of this heterogeneous syndrome, numerous clinical trials reflecting the biology of disease and catering to the advanced age of MDS patients are in development to maximize the likelihood of identifying active drugs. Addressing this diverse nature of genetic abnormalities, novel agents, and combinations are in development to formulate personalized treatment approaches for MDS patients. Myelodysplastic syndrome is categorized into subtypes that are associated with lower or higher risk for leukemic evolution, and that knowledge helps with therapy selection. Currently, as it stands, for those with higher-risk MDSs, hypomethylating agents are the first-line therapy. Allogenic stem cell transplantation represents the only potential cure for our patients with MDSs and should be considered for all eligible patients with higher-risk MDSs at the time of diagnosis. This review discusses current MDS treatment landscape, as well as new approaches in development.

Role of Midkine in Cancer Drug Resistance: Regulators of Its Expression and Its Molecular Targeting.

Molecules involved in drug resistance can be targeted for better therapeutic efficacies. Research on midkine (MDK) has escalated in the last few decades, which affirms a positive correlation between disease progression and MDK expression in most cancers and indicates its association with multi-drug resistance in cancer. MDK, a secretory cytokine found in blood, can be exploited as a potent biomarker for the non-invasive detection of drug resistance expressed in various cancers and, thereby, can be targeted. We summarize the current information on the involvement of MDK in drug resistance, and transcriptional regulators of its expression and highlight its potential as a cancer therapeutic target.

Patterns of Diagnostic Evaluation and Determinants of Treatment in Older Patients With Non-transfusion Dependent Myelodysplastic Syndromes.

BACKGROUND: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. PATIENTS AND METHODS: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and investigative procedures performed. We conducted a logistic regression analysis to identify correlates associated with receipt of DE and treatment. RESULTS: Of 16 851 patients with MDS, 51% underwent DE. patients with MDS with no cytopenia (n = 3908) had the lowest uptake of DE (34.7%). Compared to patients with no cytopenia, those with any cytopenia had nearly 3 times higher odds of receiving DE [adjusted odds ratio (AOR), 2.81: 95% CI, 2.60-3.04] and the odds were higher for men than for women [AOR, 1.39: 95%CI, 1.30-1.48] and for Non-Hispanic Whites [vs. everyone else (AOR, 1.17: 95% CI, 1.06-1.29)]. The CART showed DE as the principal discriminating node, followed by the presence of any cytopenia for receiving MDS treatment. The lowest percentage of treatment was observed in patients without DE, at 14.6%. CONCLUSION: In this select older patients with MDS, we identified disparities in accurate diagnosis by demographic and clinical factors. Receipt of DE influenced subsequent treatment but not survival.

Clonal Hematopoiesis of Indeterminate Potential: Current Understanding and Future Directions.

PURPOSE OF REVIEW: This article summarizes the current knowledge about clonal hematopoiesis of indeterminate potential (CHIP), its association with cardiovascular disease (CVD), and other outcomes, pathogenesis, postulated mechanisms of various pathologies, current knowledge gaps, possible targets of intervention, and therapeutic implications. RECENT FINDINGS: Recently, a common age-related hematological entity known as CHIP has been identified as the independent risk factor for CVD. CHIP is defined as the presence of clonally expanded blood cells involving leukemogenic mutations without the evidence of malignancy. CHIP is known to increase the inflammatory state which in turn is thought to be responsible for increased risk of CVD. Apart from CVD and malignancy, CHIP is also associated with pulmonary embolism, COPD, CKD, stroke, altered metabolism, obesity, liver disease, and increased all-cause mortality. At the same time surprisingly, CHIP is found to have positive outcomes in bone marrow transplant patients and similar reciprocal association with Alzheimer's disease. The risk of CVD and cancer increases with the advancing age, and these two are the leading causes of death in the USA. CHIP is an independent risk factor for CVD development. Most patients with CHIP have somatic clonal mutations in epigenetic regulators, DNA repair genes, or regulatory tyrosine kinases without evidence of overt hematological malignancy. CHIP portends increased risk for leukemia development and carries twofold increased risk of CVD including CAD, MI, and poor prognosis in heart failure. CHIP is associated with various other pathologies making CHIP an area of active research interest in recent years. Current research efforts aim to bridge many knowledge gaps in understanding of CHIP that still exist.

ATXN3 controls DNA replication and transcription by regulating chromatin structure.

The deubiquitinating enzyme Ataxin-3 (ATXN3) contains a polyglutamine (PolyQ) region, the expansion of which causes spinocerebellar ataxia type-3 (SCA3). ATXN3 has multiple functions, such as regulating transcription or controlling genomic stability after DNA damage. Here we report the role of ATXN3 in chromatin organization during unperturbed conditions, in a catalytic-independent manner. The lack of ATXN3 leads to abnormalities in nuclear and nucleolar morphology, alters DNA replication timing and increases transcription. Additionally, indicators of more open chromatin, such as increased mobility of histone H1, changes in epigenetic marks and higher sensitivity to micrococcal nuclease digestion were detected in the absence of ATXN3. Interestingly, the effects observed in cells lacking ATXN3 are epistatic to the inhibition or lack of the histone deacetylase 3 (HDAC3), an interaction partner of ATXN3. The absence of ATXN3 decreases the recruitment of endogenous HDAC3 to the chromatin, as well as the HDAC3 nuclear/cytoplasm ratio after HDAC3 overexpression, suggesting that ATXN3 controls the subcellular localization of HDAC3. Importantly, the overexpression of a PolyQ-expanded version of ATXN3 behaves as a null mutant, altering DNA replication parameters, epigenetic marks and the subcellular distribution of HDAC3, giving new insights into the molecular basis of the disease.