Association Between Substance Abuse and Mental Illness Symptoms Screener (SAMISS) Scores and HIV Care Continuum Outcomes in People Newly Diagnosed with HIV in the US South.

Mental illness (MI) and substance use (SU) are highly prevalent among people with HIV (PWH) and impact care outcomes. The Substance Abuse and Mental Illness Symptoms Screener (SAMISS) is a validated screener for MI and SU, but it is unknown how screening results at entry to care correlate with subsequent HIV outcomes. This is a retrospective chart review of individuals newly diagnosed with HIV between 2016 and 2019 in a Southern US, safety-net clinic. Baseline demographics, HIV risk factors, socioeconomic variables, and SAMISS screening scores were collected. Outcomes included retention in care, achieving virologic suppression (VS), and continuous VS. Data analyses included stepwise Cox and logistic multivariate regression modeling. Among the 544 newly diagnosed PWH, mean age was 35, 76% were male, 46% non-Hispanic Black, 40% Hispanic/other. Overall, 35% screened positive for SU and 41% for MI. A positive SU (odds ratio (OR) 0.66, p = 0.04) or MI (OR 0.65, p = 0.03) SAMISS screening was associated with lower retention in care in univariate analysis, but was not statistically significant after adjusting for other variables. Positive SAMISS screening for SU and MI were both associated with reduced continuous VS in univariate and multivariate analyses (SU: adjusted OR (aOR) 0.67, p = 0.05; MI: aOR 0.66, p = 0.03). SAMISS is a useful tool for prospectively identifying individuals at risk for low retention in care and for not achieving sustained VS. Future interventions guided by SAMISS may improve HIV care continuum outcomes.

Severe Mpox Infections in People With Uncontrolled Human Immunodeficiency Virus.

In the current mpox outbreak, infections are usually self-limited. We describe 3 patients with uncontrolled HIV and mpox infections lasting months, causing debilitating lesions, complications, and death, despite initiating anti-mpox and antiretroviral therapy. Delayed treatment of mpox with antiviral agents may contribute to poor outcomes in severely immunocompromised patients.

Characteristics, Comorbidities, and Outcomes in a Multicenter Registry of Patients With Human Immunodeficiency Virus and Coronavirus Disease 2019.

BACKGROUND: People living with human immunodeficiency virus (HIV) may have numerous risk factors for acquiring coronavirus disease 2019 (COVID-19) and developing severe outcomes, but current data are conflicting. METHODS: Health-care providers enrolled consecutively, by nonrandom sampling, people living with HIV (PWH) with lab-confirmed COVID-19, diagnosed at their facilities between 1 April and 1 July 2020. Deidentified data were entered into an electronic Research Electronic Data Capture (REDCap) system. The primary endpoint was a severe outcome, defined as a composite endpoint of intensive care unit (ICU) admission, mechanical ventilation, or death. The secondary outcome was the need for hospitalization. RESULTS: There were 286 patients included; the mean age was 51.4 years (standard deviation, 14.4), 25.9% were female, and 75.4% were African American or Hispanic. Most patients (94.3%) were on antiretroviral therapy, 88.7% had HIV virologic suppression, and 80.8% had comorbidities. Within 30 days of testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 164 (57.3%) patients were hospitalized, and 47 (16.5%) required ICU admission. Mortality rates were 9.4% (27/286) overall, 16.5% (27/164) among those hospitalized, and 51.5% (24/47) among those admitted to an ICU. The primary composite endpoint occurred in 17.5% (50/286) of all patients and 30.5% (50/164) of hospitalized patients. Older age, chronic lung disease, and hypertension were associated with severe outcomes. A lower CD4 count (<200 cells/mm3) was associated with the primary and secondary endpoints. There were no associations between the ART regimen or lack of viral suppression and the predefined outcomes. CONCLUSIONS: Severe clinical outcomes occurred commonly in PWH with COVID-19. The risks for poor outcomes were higher in those with comorbidities and lower CD4 cell counts, despite HIV viral suppression. CLINICAL TRIALS REGISTRATION: NCT04333953.

Extragenital Testing for Neisseria gonorrhoeae and Chlamydia trachomatis in a Large HIV Clinic in the US South: Implementation and Epidemiology.

BACKGROUND: Rectal and oral Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) infections are common among people with HIV, especially men who have sex with men (MSM); however, GC/CT testing rates remain low in many HIV clinics. We evaluated the real-world implementation and results of extragenital nucleic acid amplification testing for GC/CT in an urban HIV clinic. METHODS: Electronic health records were reviewed for all patients 18 years or older with ≥1 outpatient visit to an HIV clinic in Dallas, TX, from February 2016 to May 2019. Extragenital nucleic acid amplification testing became available in February 2017, which was followed by active interventions to increase testing. RESULTS: Overall, 5564 individual patients were included in the preintervention period (February 2016-January 2017), 5067 in the intervention period (February 2017-August 2017), and 7030 in the postintervention period (September 2017-May 2018). Tailored education was provided to patients, and nursing and medical providers, and a self-collection protocol was implemented beginning in spring 2017. A sustained increase in extragenital GC/CT testing among MSM patients, from 70% to 87% (P < 0.01), was observed. Among MSM, overall GC positivity increased from 3.2% to 8.5% and CT positivity increased from 3.9% to 8.3%. N. gonorrhoeae/C. trachomatis infections were highest among young (<35 years) MSM, and approximately 50% of GC/CT infections diagnosed were detected by oral and rectal tests. CONCLUSIONS: Clinic-wide education and self-collection of extragenital specimens were associated with increased GC/CT testing and detection in a large HIV clinic.

Association between Federally Qualified Health Center usage and emergency department utilization among California's HIV-infected Medicaid beneficiaries, 2009.

Federally Qualified Health Centers (FQHCs) have long been important sources of care for publicly insured people living with HIV. FQHC users have historically used emergency departments (EDs) at a higher-than-average rate. This paper examines whether this greater use relates to access difficulties in FQHCs or to characteristics of FQHC users. Zero-inflated Poisson models were used to estimate how FQHC use related to the odds of being an ED user and annual number of ED visits, using claims data on 6,284 HIV-infected California Medicaid beneficiaries in 2008-2009. FQHC users averaged significantly greater numbers of annual ED visits than non-FQHC users and those with no outpatient usage (1.89, 1.59, and 1.70, respectively; P = 0.043). FQHC users had higher odds of being ED users (OR = 1.14; 95%CI 1.02-1.27). In multivariable analyses, FQHC clients had higher odds of ED usage controlling for demographic and service characteristics (OR = 1.15; 95%CI 1.02-1.30) but not when medical characteristics were included (OR = 1.08; 95%CI 0.95-1.24). Among ED users, FQHC use was not significantly associated with the number of ED visits in our models (rate ratio (RR) = 1.00; 95%CI 0.87-1.15). The overall difference in mean annual ED visits observed between FQHC and non-FQHC groups was reduced to insignificance (1.75; 95% CI 1.59-1.92 vs 1.70; 95%CI 1.54-1.85) after adjusting for demographic, service, and medical characteristics. Overall, FQHC users had higher ED utilization than non-FQHC users, but the disparity was largely driven by differences in underlying medical characteristics.

Repeating measurements by transient elastography in non-alcoholic fatty liver disease patients with high liver stiffness.

BACKGROUND AND AIM: The Baveno VI Consensus recommends repeating examination in patients with high liver stiffness measurement (LSM) by transient elastography to reduce false-positive diagnosis of advanced liver disease. We tested whether repeating transient elastography can increase the overall diagnostic accuracy. METHODS: Ninety-seven patients with non-alcoholic fatty liver disease who underwent two FibroScan examinations within 6 months prior to liver biopsy were evaluated. An LSM cut-off of 7.9 kPa was used to exclude F3-4 fibrosis. RESULTS: Seventy-eight patients had high LSM at baseline, among whom 27 had low LSM on repeated testing; only four had F3 and none had cirrhosis. In contrast, 31 of 51 patients with high LSM at both examinations had F3-4. Nineteen patients had low LSM at baseline; none of them had F3-4 regardless of the second LSM results. If we took LSM <7.9 kPa at either examination as sufficient to exclude F3-4, the negative predictive value remained high at 91%. The positive predictive value for F3-4 increased from 45% in patients with high LSM at baseline to 61% in those with high LSM at both examinations. Sensitivity analysis using different cut-offs yielded similar results, with 76% of patients with LSM >12 kPa at both examinations having F3-4. CONCLUSIONS: Transient elastography is a highly sensitive screening test to exclude F3-4 fibrosis in non-alcoholic fatty liver disease patients. One-third of patients with high LSM may have normal results on repeated examination. By repeating examination in cases with high LSM, one may spare patients from unnecessary liver biopsy.

Demographics, Behaviors, and Sexual Health Characteristics of High Risk Men Who Have Sex With Men and Transgender Women Who Use Social Media to Meet Sex Partners in Lima, Peru.

BACKGROUND: Men who have sex with men (MSM) and transgender women (TW) in Peru bear a disproportionate burden of human immunodeficiency virus (HIV) and sexually transmitted infections (STIs). In a context of quickly expanding communication technology, increasing numbers of MSM and TW are using social media applications to seek sex partners. Understanding social media users and their sex partnering practices is needed to update HIV and STI prevention programming. METHODS: In Lima, Peru, 312 MSM and 89 TW from 2 STI clinics underwent HIV and STI testing and participated in a survey of demographics, behaviors, sexual health, and social media practices. χ, t tests, and Wilcoxon Mann-Whitney tests were used to compare those with and without recent social media sex partners. RESULTS: Men who have sex with men with social media sex partners were younger, more educated, and more likely to identify as gay. They were significantly more likely to report greater numbers of sex partners, including anonymous sex partners; sex in higher-risk venues, orgies, and have rectal Neisseria gonorrhoeae or Chlamydia trachomatis infection. Transgender women with social media sex partners were also younger, more likely to participate in sex work, and have a lower rate of rapid plasma reagin positivity or history of syphilis. Participants reported using several social media sites including sexual hook-up applications, websites for gay men, pornographic websites, and chat sites, but the most common was Facebook. CONCLUSIONS: Prevention strategies targeting Peruvian MSM and TW who use social media are needed to address higher-risk sexual behavior and the high burden of STIs.

Treponema pallidum pallidum Genotypes and Macrolide Resistance Status in Syphilitic Lesions among Patients at 2 Sexually Transmitted Infection Clinics in Lima, Peru.

We report the circulating genotypes and the frequency of macrolide-resistance patterns among Treponema pallidum pallidum DNA isolated from syphilitic lesions from patients who attended 2 sexual health clinics in Lima, Peru. We implemented and used a molecular typing scheme to describe local T. pallidum pallidum strains. Among 14 specimens, subtype 14d/f was the most prevalent strain in 7 fully typed T. pallidum DNA specimens obtained from men who have sex with men and transgender women presenting with chancre-like lesions. No macrolide-resistance mutations were found in T. pallidum DNA from 10 lesions.

Risk factors for AIDS-defining illnesses among a population of poorly adherent people living with HIV/AIDS in Atlanta, Georgia.

In order to achieve the programmatic goals established in the National HIV/AIDS Strategy, virologic suppression remains the most important outcome within the HIV care continuum for individuals receiving antiretroviral therapy (ART). Therefore, clinicians have dedicated substantial resources to improve adherence and clinic retention for individuals on ART; however, these efforts should be focused first on those most at risk of morbidity and mortality related to AIDS. Our study aimed to characterize the factors that are associated with AIDS-defining illnesses (ADIs) amongst people living with HIV (PLHIV) who are poorly adherent or retained in care in order to identify those at highest risk of poor clinical outcomes. We recruited 99 adult PLHIV with a history of poor adherence to ART, poor clinic attendance, or unsuppressed viral load (VL) from the Infectious Disease Program (IDP) of the Grady Health System in Atlanta, Georgia between January and May 2011 to participate in a survey investigating the acceptability of a financial incentive for improving adherence. Clinical outcomes including the number of ADI episodes in the last five years, VLs, and CD4 counts were abstracted from medical records. Associations between survey items and number of ADIs were performed using chi-square analysis. In our study, 36.4% of participants had ≥1 ADI in the last five years. The most common ADIs were Pneumocystis jirovecii pneumonia, recurrent bacterial pneumonia, and esophageal candidiasis. Age <42.5 years (OR 2.52, 95% CI = 1.08-5.86), male gender (OR 3.51, 95% CI = 1.08-11.34), CD4 nadir <200 cells/µL (OR 11.92, 95% CI = 1.51-94.15), unemployment (OR 3.54, 95% CI = 1.20-10.40), and travel time to clinic <30 minutes (OR 2.80, 95% CI = 1.20-6.52) were all significantly associated with a history of ≥1 ADI in the last five years. Awareness of factors associated with ADIs may help clinicians identify which poorly adherent PLHIV are at highest risk of HIV-related morbidity.

Rapid Start of Antiretroviral Therapy in a Large Urban Clinic in the US South: Impact on HIV Care Continuum Outcomes and Medication Adherence.

Rapid start of antiretroviral therapy (ART) has been associated with improvement in several HIV-related outcomes in clinical trials as well as demonstration projects, but how regional and contextual differences may affect the effectiveness of this intervention necessitates further study. In this study of a large, urban, Southern US clinic-based retrospective cohort, we identified 544 patients with a new diagnosis of HIV during 2016 to 2019 and compared HIV care continuum outcomes for the first 12 months of care before and after rapid start implementation. Kaplan-Meier time-to-event curves were used to summarize time to virologic suppression, and stepwise Cox, linear, and logistic regression models were used to create multivariate models to evaluate the association between rapid start and time to virologic suppression, medication adherence, and retention in care and sustained virologic suppression, respectively. We found that rapid start was significantly associated with improved medication adherence scores (+15.37 points, 95% confidence interval [CI] 9.36-21.39, P < .01) and retention in care (adjusted odds ratio = 1.51, 95% CI 1.05-2.19, P = .03). Time to virologic suppression (median 2.46 months before, 2.56 months after rapid start) and sustained virologic suppression were not associated with rapid start in our setting. Though rapid start was associated with improved medication adherence and retention in care, more support may be needed to achieve the same outcomes seen in other studies and sustained over the entire HIV care continuum, especially in settings with significant patient and systemic barriers to care such as unstable housing, lack of Medicaid expansion, and frequent coverage interruptions.

Risk of gastrointestinal bleeding in Asian patients receiving oral anticoagulants for stroke prevention in atrial fibrillation.

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for stroke prevention in atrial fibrillation. At the Asia Pacific Advancing Patient care with EdoXaban 2023 meeting, experts shared insights on gastrointestinal bleeding with NOACs for stroke prevention in atrial fibrillation in Asian clinical practice, where NOACs have gained widespread acceptance due to their favourable profiles. Gastrointestinal bleeding risk varies amongst NOACs, emphasizing the importance of diligent patient assessment, dosage selection and vigilant monitoring. Edoxaban emerged as a viable option with a low gastrointestinal bleeding risk profile in Asian compared with non-Asian patients, supporting its continued clinical utilization for appropriate patients.

Early experiences with edoxaban for stroke prevention in atrial fibrillation in the Southeast Asia region.

Edoxaban, a once-daily, direct-acting oral anticoagulant, is approved to prevent stroke or systemic embolism in non-valvular atrial fibrillation (NVAF) and treat venous thromboembolism. The clinical benefit of edoxaban for stroke prevention in Asian patients with NVAF has been demonstrated in clinical and real-world studies. We share early clinical experiences with once-daily edoxaban and discuss its evidence-based use in patients with NVAF in Southeast Asia through several cases of patients at high risk, including frail patients, elderly patients with multiple comorbidities and patients with increased bleeding risk. These cases demonstrate the effectiveness and safety of once-daily edoxaban in patients with NVAF in Southeast Asia.

Risk Factors for SARS-CoV-2 Infection and Severe Outcomes Among People With Human Immunodeficiency Virus: Cohort Study.

Background: Studies on COVID-19 in people with HIV (PWH) have had limitations. Further investigations on risk factors and outcomes of SARS-CoV-2 infection among PWH are needed. Methods: This retrospective cohort study leveraged the national OPTUM COVID-19 data set to investigate factors associated with SARS-CoV-2 positivity among PWH and risk factors for severe outcomes, including hospitalization, intensive care unit stays, and death. A subset analysis was conducted to examine HIV-specific variables. Multiple variable logistic regression was used to adjust for covariates. Results: Of 43 173 PWH included in this study, 6472 had a positive SARS-CoV-2 result based on a polymerase chain reaction test or antigen test. For PWH with SARS-CoV-2 positivity, higher odds were found for those who were younger (18-49 years), Hispanic White, African American, from the US South, uninsured, and a noncurrent smoker and had a higher body mass index and higher Charlson Comorbidity Index. For PWH with severe outcomes, higher odds were identified for those who were SARS-CoV-2 positive, older, from the US South, receiving Medicaid/Medicare or uninsured, a current smoker, and underweight and had a higher Charlson Comorbidity Index. In a subset analysis including PWH with HIV care variables (n = 5098), those with unsuppressed HIV viral load, a low CD4 count, and no antiretroviral therapy had higher odds of severe outcomes. Conclusions: This large US study found significant ethnic, racial, and geographic differences in SARS-CoV-2 infection among PWH. Chronic comorbidities, older age, lower body mass index, and smoking were associated with severe outcomes among PWH during the COVID-19 pandemic. SARS-CoV-2 infection was associated with severe outcomes, but once we adjusted for HIV care variables, SARS-CoV-2 was no longer significant; however, low CD4 count, high viral load, and lack of antiretroviral therapy had higher odds of severe outcomes.

Consensus substrate sequence for protein-tyrosine phosphatase receptor type Z.

Protein-tyrosine phosphatase receptor type Z (Ptprz) has multiple substrate proteins, including G protein-coupled receptor kinase-interactor 1 (Git1), membrane-associated guanylate kinase, WW and PDZ domain-containing 1 (Magi1), and GTPase-activating protein for Rho GTPase (p190RhoGAP). We have identified a dephosphorylation site at Tyr-1105 of p190RhoGAP; however, the structural determinants employed for substrate recognition of Ptprz have not been fully defined. In the present study, we revealed that Ptprz selectively dephosphorylates Git1 at Tyr-554, and Magi1 at Tyr-373 and Tyr-858 by in vitro and cell-based assays. Of note, the dephosphorylation of the Magi1 Tyr-858 site required PDZ domain-mediated interaction between Magi1 and Ptprz in the cellular context. Alignment of the primary sequences surrounding the target phosphotyrosine residue in these three substrates showed considerable similarity, suggesting a consensus motif for recognition by Ptprz. We then estimated the contribution of surrounding individual amino acid side chains to the catalytic efficiency by using fluorescent peptides based on the Git1 Tyr-554 sequence in vitro. The typical substrate motif for the catalytic domain of Ptprz was deduced to be Glu/Asp-Glu/Asp-Glu/Asp-Xaa-Ile/Val-Tyr(P)-Xaa (Xaa is not an acidic residue). Intriguingly, a G854D substitution of the Magi1 Tyr-858 site matching better to the motif sequence turned this site to be susceptible to dephosphorylation by Ptprz independent of the PDZ domain-mediated interaction in cells. Furthermore, we found by database screening that the substrate motif is present in several proteins, including paxillin at Tyr-118, its major phosphorylation site. Expectedly, we verified that Ptprz efficiently dephosphorylates paxillin at this site in cells. Our study thus provides key insights into the molecular basis for the substrate recognition of Ptprz.

Feasibility of transradial coronary angiography and intervention using a single Ikari left guiding catheter for ST elevation myocardial infarction.

BACKGROUND: Transradial coronary intervention (TRI) has been widely adopted in ST elevation myocardial infarction (STEMI) patients but there is limited literature on the use of a single catheter for both diagnostic angiography and intervention. We aim to evaluate the feasibility and outcomes of TRI with a single Ikari left (IL) guiding catheter in STEMI patients. METHODS: This is a retrospective study of 362 consecutive STEMI patients from August 2007 to December 2008. We assessed the feasibility of TRI with a single IL and compared this strategy with conventional transfemoral intervention (TFI) on the following outcomes: (1) door to perfusion time, (2) total procedural duration, (3) total fluoroscopy duration, and (4) major adverse cardiac events (MACE) by intention to treat analysis. RESULTS: TRI was attempted in 185 patients. There were no failed radial cannulations. Overall success rate of primary TRI with a single IL was 96.9% and there were only 2 failures that required conversion to TFI. Compared to TFI, TRI with IL tended to a shorter median door to perfusion time, 90 (IQR 76.0 - 119.5) versus 98 (IQR 80.8 - 120.5) minutes (P = 0.07) and a shorter median procedure duration of 34 (IQR 27.0 - 45.0) versus 37 (IQR 28.0 - 49.3) minutes (P = 0.06). The median fluoroscopy duration was longer in the TRI group. MACE were comparable between the 2 groups. CONCLUSION: In experienced centers, TRI with a single IL catheter for STEMI is a feasible and effective approach and outcomes are comparable to conventional TFI.

Toxoplasmosis Encephalitis: A Cross-Sectional Analysis at a U.S. Safety-Net Hospital in the Late cART Era.

Despite decreasing incidence of toxoplasmosis encephalitis(TE) among people living with HIV(PLWH) in the late antiretroviral era, U.S. safety-net hospitals still see significant numbers of admissions for TE. Little is known about this population, their healthcare utilization and long-term outcomes. We conducted an 8-year retrospective review of PLWH with TE at a safety-net hospital. Demographics, clinical characteristics, treatments, readmissions, and outcomes were collected. We used chi-squared test to evaluate 6-month all-cause readmission and demographic/clinical characteristics. Of 38 patients identified, 79% and 40% had a new diagnosis of TE and HIV respectively. 59% had 6-month all-cause readmission. Social factors were associated with readmission (uninsured (p = 0.036), Spanish as primary language (p = 0.017), non-adherence (p = 0.030)) and not markers of clinical severity (ICU admission, steroid-use, concomitant infections, therapeutic adverse events). Despite high readmission rates, at follow-up, 60% had a complete response, 30% had a partial response. Improving TE outcomes requires focus on culturally competent, coordinated care.

Brief Report: Hospitalization Rates Among Persons With HIV Who Gained Medicaid or Private Insurance After the Affordable Care Act in 2014.

BACKGROUND: It is unknown whether gaining inpatient health care coverage had an effect on hospitalization rates among persons with HIV (PWH) after implementation of the Affordable Care Act in 2014. METHODS: Hospitalization data from 2015 were obtained for 1634 adults receiving longitudinal HIV care at 3 US HIV clinics within the HIV Research Network. All patients were engaged in care and previously uninsured and supported by the Ryan White HIV/AIDS Program in 2013. We evaluated whether PWH who transitioned to either Medicaid or private insurance in 2014 tended to have a change in hospitalization rate compared with PWH who remained uncovered and Ryan White HIV/AIDS Program supported. Analyses were performed by negative binomial regression with robust standard errors, adjusting for gender, race/ethnicity, age, HIV risk factor, CD4 count, viral load, clinic site, and 2013 hospitalization rate. RESULTS: Among PWH without inpatient health care coverage in 2013, transitioning to Medicaid [adjusted incidence rate ratio 1.26, (0.71, 2.23)] or to private insurance [0.48 (0.18, 1.28)] in 2014 was not associated with 2015 hospitalization rates, after accounting for demographics, HIV characteristics, and prior hospitalization rates. The factors significantly associated with higher hospitalization rates include age 55-64, CD4 <200 cells/µL, viral load >400 copies/mL, and 2013 hospitalization rate. CONCLUSIONS: Acquiring inpatient coverage was not associated with a change in hospitalization rates. These results provide some evidence to allay the concern that acquiring inpatient coverage would lead to increased inpatient utilization.

NEI-01-Induced Arginine Deprivation Has Potent Activity Against Acute Myeloid Leukemia Cells Both In Vitro and In Vivo.

Recent studies have revealed that targeting amino acid metabolic enzymes is a promising strategy in cancer therapy. Acute myeloid leukemia (AML) downregulates the expression of argininosuccinate synthase (ASS1), a recognized rate-limiting enzyme for arginine synthesis, and yet displays a critical dependence on extracellular arginine for survival and proliferation. This dependence on extracellular arginine, also known as arginine auxotrophy, suggests that arginine deprivation would be a treatment strategy for AML. NEI-01, a novel arginine-depleting enzyme, is capable of binding to serum albumin to extend its circulating half-life, leading to a potent anticancer activity. Here we reported the preclinical activity of NEI-01 in arginine auxotrophic AMLs. NEI-01 efficiently depleted arginine both in vitro and in vivo NEI-01-induced arginine deprivation was cytotoxic to arginine auxotrophic AML cells through induction of cell-cycle arrest and apoptosis. Furthermore, the potent anti-leukemia activities of NEI-01 were observed in three different types of mouse models including human cell line-derived xenograft, mouse cell line-derived homografts in syngeneic mice and patient-derived xenograft. This preclinical data provide strong evidence to support the potential use of NEI-01 as a therapeutic approach in AML treatment.

DNA damage and polyploidization.

A growing body of evidence indicates that polyploidization triggers chromosomal instability and contributes to tumorigenesis. DNA damage is increasingly being recognized for its roles in promoting polyploidization. Although elegant mechanisms known as the DNA damage checkpoints are responsible for halting the cell cycle after DNA damage, agents that uncouple the checkpoints can induce unscheduled entry into mitosis. Likewise, defects of the checkpoints in several disorders permit mitotic entry even in the presence of DNA damage. Forcing cells with damaged DNA into mitosis causes severe chromosome segregation defects, including lagging chromosomes, chromosomal fragments and chromosomal bridges. The presence of these lesions in the cleavage plane is believed to abort cytokinesis. It is postulated that if cytokinesis failure is coupled with defects of the p53-dependent postmitotic checkpoint pathway, cells can enter S phase and become polyploids. Progress in the past several years has unraveled some of the underlying principles of these pathways and underscored the important role of DNA damage in polyploidization. Furthermore, polyploidization per se may also be an important determinant of sensitivity to DNA damage, thereby may offer an opportunity for novel therapies.