Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.

Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer.

Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability3. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability4-6. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material-these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers.

Cardiovascular complications of rheumatoid arthritis.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients remain at higher cardiovascular (CV) risk compared to non-RA patients, driven by accelerated atherosclerosis, leading to plaque rupture and acute CV events (CVE), including heart failure (HF). It has been hypothesized that chronic inflammation is the main driving force behind such outcomes. We summarize the current evidence supporting this hypothesis, focusing on arterial disease and myocardial disease. RECENT FINDINGS: RA patients demonstrate higher prevalence of subclinical atherosclerosis (high risk plaque and arterial inflammation) compared to non-RA patients, with RA disease activity correlating independently with CVE and death. Nonischemic HF with preserved ejection fraction (HFpEF) is more common in RA compared to non-RA, with subclinical myocardial structural and functional alterations also more prevalent in RA. HFpEF and myocardial remodeling and dysfunction bear a strong and independent association with inflammatory correlates. SUMMARY: All of this suggests that inflammation contributes to enhanced risk of CVE in RA. A more accurate and specific CV risk stratification tool for RA, incorporating biomarkers or imaging, is needed. Likewise, more prospective studies outlining the trajectory from preclinical to clinical HF, incorporating biomarkers and imaging, are also needed.

Identification of Dihydromyricetin and Metabolites in Serum and Brain Associated with Acute Anti-Ethanol Intoxicating Effects in Mice.

Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin's poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC0→24) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC0→24 in male and female mice, respectively. Electrophysiology studies in α5ß3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (-12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM's anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM's potential anti-intoxicating properties.

The Role of Medical Specialization on Posttraumatic Symptoms in Pediatric Nurses.

PURPOSE: Comparison of medical specialization of repeated exposure to secondary trauma and Post-Traumatic Stress Disorder (PTSD) symptoms in pediatric nurses was examined. DESIGN AND METHODS: The PTSD Checklist-Civilian Version (PCL-C) was administered to 182 nurses over their first year on the job at a pediatric hospital (three time-points: baseline, 3 month follow-up, and 1 year follow-up). Demographic characteristics (age groups, gender, education, and race) and previous healthcare experience on whether nurses met criteria for no, partial, or full PTSD across all three time-points was examined. Differences in unit assignment on total PTSD symptoms and symptoms of each criterion of PTSD (re-experiencing, avoidance, and arousal) were also examined. RESULTS: No significant differences of both demographic characteristics and previous healthcare experience were found on these PTSD categories. However, both ICU and Hematology/Oncology units were more at risk for developing partial and full PTSD, respectively compared to other units. Nurses in the rehabilitation units had significantly higher re-experiencing, avoidance, and arousal symptoms than those assigned to medical/surgical and intensive care units. CONCLUSIONS: Results demonstrate a need for hospitals to assess why nurses from certain units are reporting more PTSD symptoms and screen for PTSD symptoms and other mental health concerns throughout their career. PRACTICE IMPLICATIONS: Being aware of which units may be more at-risk should inform unit-specific prevention and intervention programs to decrease negative outcomes, including burnout, compassion fatigue, and job dissatisfaction.

Learning support interventions for Year 1 medical students: a review of the literature.

CONTEXT: The journey through medical school can be challenging, especially for undergraduate medical students who must deal with a demanding curriculum, coupled with the demands of transitioning into adulthood. Despite experiencing learning challenges, most students succeed with appropriate learning support. Many medical schools offer learning support programmes, particularly in the latter years, but it has been suggested that such support could be more beneficial, especially during the initial years. OBJECTIVES: This review explores learning support intervention programmes used to address learning challenges and deficits in the first year of medical school. Additionally, we propose a potential framework for supporting learning during the first year of medical school. METHODS: We searched PubMed, Web of Science, MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ERIC (Educational Resources Information Centre), Academic Search Premier and Google Scholar using the search terms 'learning support', 'learning challenge', 'remediation', 'change', 'medical education' and 'first year'. We developed and used a review matrix to record the main elements of each article. We also coded the matrix to identify emerging themes. RESULTS: The main themes that emerged from the study were 'intervention approaches', 'area of intervention', 'intervention strategies', 'intervention dose' and 'intervention outcomes'. INTERVENTIONS: (i) used proactive-deficit, reactive-deficit and proactive-developmental approaches; (ii) addressed content knowledge, academic success skills, personal and professional skills and programme-related elements; (iii) utilised faculty staff-facilitated, peer-facilitated, support staff-facilitated, experiential placement, self-study and reduced-load strategies; (iv) varied in length from 5 weeks to 2 years, and (v) generally showed positive results. CONCLUSIONS: This review has identified the main components of learning support interventions used for Year 1 medical students. Interventions, however, are generally not grounded on empirical assessment that elucidates the nature of the challenges faced by students. Future research should provide empirical understanding of the learning challenges to be addressed.

Nab-paclitaxel-induced cystoid macular edema in a patient with pre-existing optic neuropathy.

Paclitaxel is a widely used chemotherapy agent that has rarely been associated with ophthalmic toxicities. Cystoid macular edema is one such rare side effect of paclitaxel therapy. Its pathophysiology remains poorly understood. Here, we report on a 69-year-old woman who developed cystoid macular edema associated with the albumin-bound formulation of paclitaxel after several months of therapy for breast cancer. After 2 months of drug withdrawal, her vision improved and there was a significant improvement in the macular edema by imaging with spectral-domain optical coherence tomography. Oncologists using taxane agents should be aware of this rare adverse outcome for timely patient referral to an ophthalmologist and appropriate treatment to preserve a patient's visual acuity.

Diagnostic errors related to acute abdominal pain in the emergency department.

OBJECTIVE: Diagnostic errors in the emergency department (ED) are harmful and costly. We reviewed a selected high-risk cohort of patients presenting to the ED with abdominal pain to evaluate for possible diagnostic errors and associated process breakdowns. DESIGN: We conducted a retrospective chart review of ED patients >18 years at an urban academic hospital. A computerised 'trigger' algorithm identified patients possibly at high risk for diagnostic errors to facilitate selective record reviews. The trigger determined patients to be at high risk because they: (1) presented to the ED with abdominal pain, and were discharged home and (2) had a return ED visit within 10 days that led to a hospitalisation. Diagnostic errors were defined as missed opportunities to make a correct or timely diagnosis based on the evidence available during the first ED visit, regardless of patient harm, and included errors that involved both ED and non-ED providers. Errors were determined by two independent record reviewers followed by team consensus in cases of disagreement. RESULTS: Diagnostic errors occurred in 35 of 100 high-risk cases. Over two-thirds had breakdowns involving the patient-provider encounter (most commonly history-taking or ordering additional tests) and/or follow-up and tracking of diagnostic information (most commonly follow-up of abnormal test results). The most frequently missed diagnoses were gallbladder pathology (n=10) and urinary infections (n=5). CONCLUSIONS: Diagnostic process breakdowns in ED patients with abdominal pain most commonly involved history-taking, ordering insufficient tests in the patient-provider encounter and problems with follow-up of abnormal test results.

Transferring Fungi to a Deuterium-Enriched Medium Results in Assorted, Conditional Changes in Secondary Metabolite Production.

Deuterium is one of the few stable isotopes that have the capacity to significantly alter a compound's chemical and biological properties. The addition of a single neutron to a protium atom results in the near doubling of its mass, which gives rise to deuterium's characteristic isotope effects. Since the incorporation of deuterium into organic substrates is known to alter enzyme/protein-substrate interactions, we tested the extent to which deuterium enrichment would modify fungal secondary metabolite production. Several fungal cultures were tested, and in all cases their secondary metabolomes were marked by changes in natural product production. Workup of one Aspergillus sp. grown under deuterium-enrichment conditions resulted in the production of several secondary metabolites not previously detected from the fungus. Bioassay testing revealed that in comparison to the inactive crude fungal extract derived from growing the fungus under non-deuterium-enriched conditions, an extract derived from the same isolate cultured in a deuterium-enriched medium inhibited methicillin-resistant Staphylococcus aureus. Using an assortment of NMR and mass spectrometry experiments, we were able to identify the bacterial inhibitor as an isotope-labeled version of pigmentosin A (6). Five additional isotopically labeled metabolites were also obtained from the fungus including brevianamide F (1), stephacidin A (2), notoamide D (3), notoamide L (4), and notoamide C (5). Given the assorted changes observed in the secondary metabolite profiles of this and other fungi grown in deuterium-enriched environments, as well as the fact that 1 and 3-6 had not been previously observed from the Aspergillus sp. isolate used in this study, we propose that deuterium enrichment might offer an effective method for further expanding a fungus's chemical diversity potential.

Polyketide glycosides from Bionectria ochroleuca inhibit Candida albicans biofilm formation.

One of the challenges presented by Candida infections is that many of the isolates encountered in the clinic produce biofilms, which can decrease these pathogens' susceptibilities to standard-of-care antibiotic therapies. Inhibitors of fungal biofilm formation offer a potential solution to counteracting some of the problems associated with Candida infections. A screening campaign utilizing samples from our fungal extract library revealed that a Bionectria ochroleuca isolate cultured on Cheerios breakfast cereal produced metabolites that blocked the in vitro formation of Candida albicans biofilms. A scale-up culture of the fungus was undertaken using mycobags (also known as mushroom bags or spawn bags), which afforded four known [TMC-151s C-F (1-4)] and three new [bionectriols B-D (5-7)] polyketide glycosides. All seven metabolites exhibited potent biofilm inhibition against C. albicans SC5314, as well as exerted synergistic antifungal activities in combination with amphotericin B. In this report, we describe the structure determination of the new metabolites, as well as compare the secondary metabolome profiles of fungi grown in flasks and mycobags. These studies demonstrate that mycobags offer a useful alternative to flask-based cultures for the preparative production of fungal secondary metabolites.

Measuring success: results from a national survey of recruitment and retention initiatives in the nursing workforce.

OBJECTIVES: The purpose of this study was to identify common components of diversity pipeline programs across a national sample of nursing institutions and determine what effect these programs have on increasing underrepresented minority enrollment and graduation. DESIGN: Linked data from an electronic survey conducted November 2012 to March 2013 and American Association of Colleges of Nursing baccalaureate graduation and enrollment data (2008 and 2012). PARTICIPANTS: Academic and administrative staff of 164 nursing schools in 26 states, including Puerto Rico in the United States. METHODS: Chi-square statistics were used to (1) describe organizational features of nursing diversity pipeline programs and (2) determine significant trends in underrepresented minorities' graduation and enrollment between nursing schools with and without diversity pipeline programs RESULTS: Twenty percent (n = 33) of surveyed nursing schools reported a structured diversity pipeline program. The most frequent program measures associated with pipeline programs included mentorship, academic, and psychosocial support. Asian, Hispanic, and Native Hawaiian/Pacific Islander nursing student enrollment increased between 2008 and 2012. Hispanic/Latino graduation rates increased (7.9%-10.4%, p = .001), but they decreased among Black (6.8%-5.0%, p = .004) and Native American/Pacific Islander students (2.1 %-0.3%, p ≥ .001). CONCLUSIONS: Nursing diversity pipeline programs are associated with increases in nursing school enrollment and graduation for some, although not all, minority students. Future initiatives should build on current trends while creating targeted strategies to reverse downward graduation trends among Black, Native American, and Pacific Island nursing students.

Associations of galectin-3 levels with measures of vascular disease in patients with rheumatoid arthritis.

OBJECTIVES: Galectin-3 is a beta-galactoside-binding lectin and is a marker of cardiovascular disease (CVD) in the general population. It may also play a role in joint inflammation. We asked whether serum galectin-3 is a useful marker of subclinical vascular disease in patients with rheumatoid arthritis (RA). METHODS: RA patients without clinical CVD underwent assessment of coronary artery calcium (CAC) score, aortic inflammation (using 18Fluorodeoxyglucose positron emission-computed tomography [FDG PET/CT]), and myocardial flow reserve (MFR). Aorta FDG uptake was measured as standardized uptake values (SUV). Generalized linear models were constructed to explore the associations of galectin-3 levels with CAC score, aortic SUV, and MFR. RESULTS: A total of 124 RA patients (mean age 57; 82 % women, 45 % Hispanic; median RA duration 6.8 years; 75 % seropositive; median CDAI 16; 33 % on prednisone; 89 % on DMARDs; median CAC score 0; median aorta SUV 2.59; mean MFR 2.86; median galectin-3 level 8.54 ng/mL) were analyzed. In univariable analysis, higher galectin-3 levels were associated with higher aortic SUV (p = 0.007) but CAC score and MFR were not. In multivariable analysis, higher galectin-3 level remained significantly associated with higher aortic SUV (ß Coefficient=0.1786, p value=0.002). CONCLUSION: In our cohort of RA patients without clinical CVD, higher serum galectin-3 levels were independently associated with higher levels of aortic inflammation, but not CAC score or MFR. This suggests that galectin-3 may be a biomarker for an inflammatory and potentially reversible stage, but not a later (calcified) stage, of atherosclerosis in patients with RA.

Retrieval augmented scientific claim verification.

Objective: To automate scientific claim verification using PubMed abstracts. Materials and Methods: We developed CliVER, an end-to-end scientific Claim VERification system that leverages retrieval-augmented techniques to automatically retrieve relevant clinical trial abstracts, extract pertinent sentences, and use the PICO framework to support or refute a scientific claim. We also created an ensemble of three state-of-the-art deep learning models to classify rationale of support, refute, and neutral. We then constructed CoVERt, a new COVID VERification dataset comprising 15 PICO-encoded drug claims accompanied by 96 manually selected and labeled clinical trial abstracts that either support or refute each claim. We used CoVERt and SciFact (a public scientific claim verification dataset) to assess CliVER's performance in predicting labels. Finally, we compared CliVER to clinicians in the verification of 19 claims from 6 disease domains, using 189 648 PubMed abstracts extracted from January 2010 to October 2021. Results: In the evaluation of label prediction accuracy on CoVERt, CliVER achieved a notable F1 score of 0.92, highlighting the efficacy of the retrieval-augmented models. The ensemble model outperforms each individual state-of-the-art model by an absolute increase from 3% to 11% in the F1 score. Moreover, when compared with four clinicians, CliVER achieved a precision of 79.0% for abstract retrieval, 67.4% for sentence selection, and 63.2% for label prediction, respectively. Conclusion: CliVER demonstrates its early potential to automate scientific claim verification using retrieval-augmented strategies to harness the wealth of clinical trial abstracts in PubMed. Future studies are warranted to further test its clinical utility.

Closing the gap between open source and commercial large language models for medical evidence summarization.

Large language models (LLMs) hold great promise in summarizing medical evidence. Most recent studies focus on the application of proprietary LLMs. Using proprietary LLMs introduces multiple risk factors, including a lack of transparency and vendor dependency. While open-source LLMs allow better transparency and customization, their performance falls short compared to the proprietary ones. In this study, we investigated to what extent fine-tuning open-source LLMs can further improve their performance. Utilizing a benchmark dataset, MedReview, consisting of 8161 pairs of systematic reviews and summaries, we fine-tuned three broadly-used, open-sourced LLMs, namely PRIMERA, LongT5, and Llama-2. Overall, the performance of open-source models was all improved after fine-tuning. The performance of fine-tuned LongT5 is close to GPT-3.5 with zero-shot settings. Furthermore, smaller fine-tuned models sometimes even demonstrated superior performance compared to larger zero-shot models. The above trends of improvement were manifested in both a human evaluation and a larger-scale GPT4-simulated evaluation.

STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response.

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

Left ventricular remodeling in rheumatoid arthritis patients without clinical heart failure.

Rheumatoid arthritis (RA) patients have a 1.5- to twofold higher risk of developing heart failure (HF) and a twofold increased risk of HF-associated mortality compared to those without RA. HF is preceded subclinically by left ventricular (LV) remodeling in the general population. There is a relative absence of prospective studies following RA patients from pre-clinical to clinical HF as well as prospective studies of LV remodeling in RA without clinical HF. In our study, 158 RA patients without clinical HF were enrolled and underwent transthoracic echocardiography (TTE) at baseline and on follow-up between 4 and 6 years. Extensive characterization of RA disease activity and cardiovascular risk factors were performed. LV remodeling was prevalent at 40% at baseline and increased to 60% over time. Higher levels of interleukin-6 (IL 6) were associated with concentric LV remodeling on follow-up. The use of tocilizumab was also significantly associated with baseline LV remodeling (relative wall thickness). These findings suggest a role for IL-6 as a biomarker for LV remodeling in RA patients without clinical HF. Future research should focus on prospective follow-up of LV remodeling and the effects of IL-6 inhibition on LV remodeling in RA patients.

Acylpyrazoline-Based Third-Generation Selective Antichlamydial Compounds with Enhanced Potency.

Chlamydiae are obligate intracellular Gram-negative bacteria and widespread pathogens in humans and animals. Broad-spectrum antibiotics are currently used to treat chlamydial infections. However, broad-spectrum drugs also kill beneficial bacteria. Recently, two generations of benzal acylhydrazones have been shown to selectively inhibit chlamydiae without toxicity to human cells and lactobacilli, which are dominating, beneficial bacteria in the vagina of reproductive-age women. Here, we report the identification of two acylpyrazoline-based third-generation selective antichlamydials (SACs). With minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of 10-25 µM against Chlamydia trachomatis and Chlamydia muridarum, these new antichlamydials are 2- to 5-fold more potent over the benzal acylhydrazone-based second-generation selective antichlamydial lead SF3. Both acylpyrazoline-based SACs are well tolerated by Lactobacillus, Escherichia coli, Klebsiella, and Salmonella as well as host cells. These third-generation selective antichlamydials merit further evaluation for therapeutic application.

STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity.

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as Stat3 deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated Stat3 deletion in 20% of the hematopoietic compartment. Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to Stat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells revealed altered transcriptional responses in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient Lin-ckit+Sca1+ cells accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.