Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Pazopanib elicits remarkable response in metastatic porocarcinoma: a functional precision medicine approach.

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.

Concordance of the ACR TI-RADS Classification With Bethesda Scoring and Histopathology Risk Stratification of Thyroid Nodules.

Importance: Although most thyroid nodules are benign, 10% to 15% of them harbor cancer. Thyroid ultrasonography is useful for risk stratification of nodules, and American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) classification provides recommendations for fine-needle aspiration cytology (FNAC) based on objective ultrasonographic features of these nodules. Objective: To validate the concordance of ACR TI-RADS classification with Bethesda classification and histopathology. Design, Setting, and Participants: This retrospective cohort study was performed to evaluate the concordance of ACR TI-RADS classification with Bethesda classification and histopathology and was conducted in Singapore General Hospital Outpatient Otolaryngology clinic in March 2021 to May 2021. Data analysis was performed in May 2021. Main Outcomes and Measures: Results were deemed concordant when ACR TI-RADS recommendations aligned with Bethesda scores. Conversely, results were classified as nonconcordant with Bethesda scores and/or histopathology results when nodules that were recommended for FNAC yielded benign results or nodules that were not recommended for FNAC yielded malignant results. Results: A total of 446 patients (370 women [83%]; mean [range] age, 60 [24-89] years) who underwent ultrasonography of the thyroid and ultrasonography-guided thyroid FNACs were identified. A total of 492 of 630 nodules (78.1%) were benign on FNAC (Bethesda II). Score 3 ACR TI-RADS nodules yielded the highest negative predictive values: 94.6% (95% CI, 92.9%-95.9%; P < .001) compared with Bethesda scoring and 100.0% (95% CI, 15.8%-100.0%; P = .003) compared with histopathology. Score 4 or 5 ACR TI-RADS nodules yielded positive predictive values of 2.8% and 16.2%, respectively, compared with Bethesda scoring and 6.1% and 66.7%, respectively, compared with histopathology. Small (<1.5 cm) ACR TI-RADS nodules of scores of 4 and 5 that were not recommended for FNAC yielded a malignant risk of 5.7% and 25.0% on Bethesda 5 and 6, respectively. On surgical excision, 5 of 46 (10.9%) ACR TI-RADS 4 nodules and 15 of 21 (71.4%) of ACR TI-RADS 5 nodules were confirmed to be malignant. Among nodules initially not recommended for FNAC, histopathology-proven cancer was found in 4 of 13 (30.7%) and 3 of 6 (50.0%) of nodules, respectively. Conclusions and Relevance: These findings suggest that ACR TI-RADS score 3 nodules have a low risk of cancer and should be considered for FNAC only if nodules are 2.5 cm or larger. Patients with small (<1.5 cm) ACR TI-RADS 4 and 5 nodules should be appropriately counseled for FNAC to exclude cancer.

Lung Cancer Screening Penetration in an Urban Underserved County.

PURPOSE: To compare residential geography, sex, socioeconomic status (SES), and race/ethnicity of patients screened at Montefiore's Lung Cancer Screening Program with those of patients diagnosed with lung cancer, assessing whether screening efforts are appropriately focused. METHODS: This retrospective cohort study involved patients within a multisite urban medical center undergoing lung cancer screening or diagnosed with lung cancer from January 1, 2015 to December 31, 2019. Inclusion criteria were residence within the Bronx, NY and age between 55 and 80 years. Institutional review board approval was obtained. Data were analyzed using the Wilcoxon two-sample t test and χ2. RESULTS: The cohorts comprised 1568 (50.3%) women and 1551 (49.7%) men (mean age 65.6 ± 6.16). The Southeast Bronx had the most diagnosed lung cancers (29.96%) and screenings (31.22%). Sex did not significantly differ (p = 0.053). Cancer and screening cohorts were from impoverished neighborhoods with mean SES of - 3.11 ± 2.78 and - 3.44 ± 2.80 (p < 0.01). The lower tier SES neighborhoods demonstrated more patients in the screening cohort than cancer cohort (p = 0.01). Both cohorts included a majority of Hispanic patients, although race/ethnicity differed significantly (p = 0.01). Lower SES neighborhoods showed no significant difference in race/ethnicity between cancer and screening cohorts (p = 0.262). CONCLUSION: Though statistically significant differences were found between cohorts, likely due to sample size, few clinically meaningful differences were found, implying our lung cancer screening program was effective in reaching the desired population. Demographics-based programs should be considered in global efforts to screen vulnerable populations.

The Role of Physician-Directed Duplex after Brachial Plexus Block in Arteriovenous Fistula Creation.

BACKGROUND: Best practice guidelines for dialysis access creation emphasize distal sites and autogenous tissue before more proximal sites and synthetic shunts. Pre-operative vein mapping is a useful modality to evaluate optimal access location; however, vein size is often underestimated secondary to patient hypovolemia, room temperature, and basal vascular tone. Supraclavicular brachial plexus blocks (BPB) are routinely performed to provide surgical anesthesia but also have known vasodilatory effects. Although many surgeons use both techniques, most do not repeat vein mapping after BPB to re-evaluate targets after block-mediated vasodilation. Therefore, we evaluated whether the role of physician-directed vein mapping after BPB resulted in more favorable access creations. METHODS: All patients who underwent primary ipsilateral access creation with physician-directed post-block duplex between 2017 and 2018 were evaluated. Vein mapping was reviewed for "theoretical access location" using the criterion of >2.5 mm vessels. Fistula preference was analogous to current indications with the following order of preference: wrist radiocephalic, forearm radiocephalic, brachiocephalic, brachiobasilic, and finally prosthetic graft. RESULTS: Forty-three patients met inclusion criteria. In total, physician-directed duplex after regional block resulted in the creation of higher preference accesses than predicted in 62.8% of patients. In 34.9% the access was at the predicted level and only 2.3% were at a lower preference. Furthermore, there were no differences in the maturation rates between accesses placed at higher preference locations than predicted compared to those at expected sites (74% vs. 79%, P = 0.38). The overall revision rate for higher preference access was 22.2% compared to 23.1% for equal/lower preference accesses. Of those accesses that failed, 83.3% of new accesses were created at the original theoretical location while 17.7% required placement of a lower preference access. CONCLUSIONS: Physician-directed ultrasound after BPB allows for identification of more preferential targets for access creation compared to pre-operative vein mapping. For access created at more preferential locations than pre-operatively predicted prior to BPB, there was no difference in maturation rates compared to those created at the theoretical vein mapping location.

Healthy versus unhealthy comfort eating for psychophysiological stress recovery in low-income Black and Latinx adults.

Low-income Black and Latinx individuals are disproportionately vulnerable to chronic stress and metabolic disease. Evidence suggests that these populations engage in elevated levels of comfort eating (i.e., eating comforting food to alleviate stress), which can harm diet quality. For this reason, many interventions discourage comfort eating. However, if comfort eating does indeed buffer stress, it may be a protective health behavior, particularly if healthy foods (e.g., strawberries) buffer stress as effectively as traditional unhealthy comfort foods (e.g., brownies). By choosing healthy foods, people may be able to simultaneously improve their nutrition and reduce their stress levels, both of which have the potential to reduce health disparities among chronically stressed populations. The present study tested the efficacy of healthy and unhealthy comfort eating for improving psychophysiological stress recovery. A sample of low-income Black and Latinx individuals (N = 129) were randomly assigned to consume a healthy food (e.g., grapes), unhealthy comfort food (e.g., chips), or no food after exposure to a laboratory stressor. Throughout, we measured participants' psychophysiological stress responses, including self-reported stress, rumination, autonomic nervous system activation (i.e., electrodermal activity (EDA), heart rate variability (HRV)) and neuroendocrine responses (i.e., salivary cortisol). We compared participants' stress recovery trajectories by condition and found no significant group differences (p = 0.12 for self-reported stress; p = 0.92 for EDA; p = 0.22 for HRV, p = 1.00 for cortisol). Participants in all conditions showed decreases in self-reported stress and in cortisol post-stressor (ps < 0.01), but rates of decline did not differ by condition (i.e., healthy or unhealthy comfort food, brief no-food waiting period). Although null, these results are important because they challenge the widely-held assumption that comfort foods help people decrease stress.

Weight stigma and health behaviors: evidence from the Eating in America Study.

BACKGROUND: Weight stigma is pervasive across the U.S. and is associated with poor health outcomes including all-cause mortality. One potential reason that weight stigma may be detrimental to health is that it begets poorer health behaviors. Therefore, the present study tested for associations between weight stigma and four health behaviors (i.e., eating behavior, alcohol use, sleep disturbance, and physical activity), while controlling for BMI and other potential confounds. SUBJECTS/METHODS: Participants (N = 2022) in the U.S. were recruited for the Eating in America Study using a Qualtrics panel between December 2019 and January 2020 and were census-matched according to national quotas for age, gender, income, race/ethnicity, and census region. Participants completed questionnaires about weight stigma, health behaviors, demographics, and anthropometric measurements. The current study employed a two-stage investigation: exploratory analyses were first performed on a random sample of the dataset (n = 438), then the remaining unexamined data were used to conduct confirmatory analyses that were preregistered on the Open Science Framework. RESULTS: Controlling for BMI, weight stigma was significantly associated with greater disordered eating (b = 0.34, 95% CI [0.31, 0.38], p < 0.001), comfort eating (b = 0.32, 95% CI [0.25, 0.39], p < 0.001), sleep disturbance (b = 0.27, 95% CI [0.20, 0.33], p < 0.001), and alcohol use (b = 0.30, 95% CI [0.11, 0.49], p = 0.002), but not lower physical activity (b = -0.04, 95% CI [-0.13, 0.05], p = 0.402) for individuals across the weight spectrum. BMI and perceived weight status significantly moderated the effects of weight stigma on disordered eating and alcohol use. No gender differences were found. These confirmatory analyses partially replicated the exploratory stage 1 findings. CONCLUSIONS: This study provides preliminary evidence that weight stigma is linked to several poor health behaviors, which may impact physical health.

Management of arterial dissections in 12 patients during transarterial chemoembolization and yttrium-90 selective internal radiotherapy for primary and secondary liver tumours.

OBJECTIVE: To describe rates and management strategies of arterial dissections in transarterial chemoembolization (TACE) and Yttrium-90 selective internal radiotherapy (90Y SIRT) for primary and secondary liver tumours. MATERIALS AND METHODS: This retrospective review included 1377 hepatic angiographies between May 2010 and June 2015 in a single centre for TACE and 90Y SIRT of liver tumours. The angiogram results, management, treatment outcomes and follow-up angiography/imaging findings were recorded. RESULTS AND DISCUSSION: Twelve cases of arterial dissections (12/1377, 0.87%) were documented. Three dissections (3/633, 0.47%) occurred during TACE, seven (7/449, 1.56%) during pre-treatment planning angiographies (PTPA) for 90Y SIRT, and two (2/249, 0.80%) during the treatment procedure of 90Y SIRT. The preferred management strategy was to manoeuvre past the dissection and complete the procedure, which was achieved in six patients (50%). Angioplasty with stenting was performed in one patient. In three patients, the procedure was held off for up to 3 months to allow the dissection to heal before repeating the procedure. A dissection that occurred during PTPA was detected only when the patient returned for 90Y SIRT. PTPA was immediately repeated for this patient. The last patient opted for sorafenib. Residual 50% stenosis was seen in one patient on follow-up hepatic angiography, but he was otherwise asymptomatic. In the remaining patients, no residual dissection or clinical sequelae was observed on follow-up. CONCLUSION: Arterial dissection is a rare but important complication of transarterial locoregional therapy. Where possible, attempts should be made at completing the therapy. Deferring treatment can be considered as dissections usually heal within 3 months. LEVEL OF EVIDENCE: Level 4, case series.

Letter to the editor: Comment on a case report of thermal injury to spinal cord, a rare complication of percutaneous microwave spine tumour ablation.

Microwave ablation of the spine is an effective treatment option for patients with symptomatic osseous metastases. It is an increasingly common procedure in clinical practice and can be performed in conjunction with other procedures such as vertebroplasty and nerve root blocks. Multiple studies have demonstrated the safety and efficacy of the percutaneous ablation; however potential complications can arise. Thermal injury to the spinal cord is a rare but serious known complication which has severe consequences to the patient. Multiple strategies can be adopted to reduce the rate of complications. We aim to discuss the various technical considerations when performing percutaneous ablation of spinal tumours to decrease the risks of complications.

Performance and acceptability of self-collected human papillomavirus testing among women living with HIV.

OBJECTIVE: To assess the validity, reliability, and acceptability of self-collected human papillomavirus (HPV) tests in women living with HIV (WLHIV) in the United States. METHODS: WLHIV ≥30 years of age underwent self-collected (clinic and home) and clinician-collected HPV tests. Sensitivity and specificity analyses were performed using the clinician-collected HPV tests as the comparator. The unweighted kappa statistic was used to evaluate the validity and reliability of self-collected HPV testing, and the level of agreement between the clinician-collected mRNA test and a DNA test that was used for routine care. A 13-question survey was used to assess acceptability. RESULTS: Among the 70 participants, the median age was 50 years, 75% had an undetectable HIV RNA, and 11% had a CD4 count of <200 cells/µl. Nearly 63% had at least one positive HPV test. The sensitivity and specificity of the self-collected HPV test were 84.6% (95% confidence interval (CI) 65.1-95.6%) and 62.9% (95% CI 44.9-78.5%), respectively (κ=0.5, 95% CI 0.2-0.7). The agreement between the two self-collected tests was good (κ=0.8, 95% CI 0.5-1.0). There was good agreement between clinician-collected mRNA tests and DNA tests (κ=0.8, 95% CI 0.7-1.0). Self-collection was highly acceptable. CONCLUSIONS: Among WLHIV, self-collected HPV tests had good sensitivity and moderate specificity compared to clinician-collected HPV tests. The reliability between self-collected testing locations was good. Self-collected HPV testing had high acceptability.

Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling.

The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.

Alcohol sedation in adult Drosophila is regulated by Cysteine proteinase-1 in cortex glia.

Although numerous studies have demonstrated that neuronal mechanisms regulate alcohol-related behaviors, very few have investigated the direct role of glia in behavioral responses to alcohol. The results described here begin to fill this gap in the alcohol behavior and gliobiology fields. Since Drosophila exhibit conserved behavioral responses to alcohol and their CNS glia are similar to mammalian CNS glia, we used Drosophila to begin exploring the role of glia in alcohol behavior. We found that knockdown of Cysteine proteinase-1 (Cp1) in glia increased Drosophila alcohol sedation and that this effect was specific to cortex glia and adulthood. These data implicate Cp1 and cortex glia in alcohol-related behaviors. Cortex glia are functionally homologous to mammalian astrocytes and Cp1 is orthologous to mammalian Cathepsin L. Our studies raise the possibility that cathepsins may influence behavioral responses to alcohol in mammals via roles in astrocytes.

Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells.

Acute promyelocytic leukemia (APL) is characterized by arrested differentiation of promyelocytes. Patients treated with all-trans retinoic acid (ATRA) alone experience relapse, while patients treated with ATRA and arsenic trioxide (ATO) are often relapse-free. This suggests sustained changes have been elicited by the combination therapy. To understand the lasting effects of the combination therapy, we compared the effects of ATRA and ATO on NB4 and ATRA-resistant NB4-MR2 APL cells during treatment versus post treatment termination. After treatment termination, NB4 cells treated with ATRA or ATO reverted to non-differentiated cells, while combination-treated cells remained terminally differentiated. This effect was diminished in NB4-MR2 cells. This suggests combination treatment induced more permanent changes. Combination treatment induced higher expression of target genes (e.g., transglutaminase 2 and retinoic acid receptor beta), which in NB4 cells was sustained post treatment termination. To determine whether sustained epigenetic changes were responsible, we quantified the enrichment of histone modifications by chromatin immunoprecipitation, and CpG methylation by bisulfite-pyrosequencing. While ATRA and combination treatment induced similar histone acetylation enrichment, combination treatment induced greater demethylation of target genes, which was sustained. Therefore, sustained demethylation of target genes by ATRA and ATO combination treatment is associated with lasting differentiation and gene expression changes.

Tuberculosis infection risk, preventive therapy care cascade and incidence of tuberculosis disease in healthcare workers at Maputo Central Hospital.

BACKGROUND: Mozambican healthcare workers have high rates of latent and active tuberculosis, but occupational screening for tuberculosis is not routine in this setting. Furthermore, the specificity of tuberculin skin testing in this population compared with interferon gamma release assay testing has not been established. METHODS: This study was conducted among healthcare workers at Maputo Central Hospital, a public teaching quaternary care hospital in Mozambique. With a cross sectional study design, risk factors for tuberculosis were assessed using multivariable logistic regression. The care cascade is reported for participants who were prescribed six months of isoniazid preventive therapy for HIV or highly reactive testing for latent tuberculosis infection. The agreement of interferon-gamma release assay results with positive tuberculin skin testing was calculated. RESULTS: Of 690 screened healthcare workers, three (0.4%) had active tuberculosis and 426 (61.7%) had latent tuberculosis infection. Less education, age 35-49, longer hospital service, and work in the surgery department were associated with increased likelihood of being tuberculosis infected at baseline (p < 0.05). Sex, Bacillus Calmette-Guerin vaccination, HIV, outside tuberculosis contacts, and professional category were not. Three new cases of active tuberculosis developed during the follow-up period, two while on preventive therapy. Among 333 participants offered isoniazid preventive therapy, five stopped due to gastrointestinal side effects and 181 completed treatment. For HIV seropositive individuals, the agreement of interferon gamma release assay positivity with positive tuberculin skin testing was 50% among those with a quantitative skin test result of 5-10 mm, and among those with a skin test result ≥10 mm it was 87.5%. For HIV seronegative individuals, the agreement of interferon gamma release assay positivity with a tuberculin skin test result of 10-14 mm was 63.6%, and for those with a quantitative skin test result ≥15 mm it was 82.2%. CONCLUSIONS: There is a high prevalence of tuberculosis infected healthcare workers at Maputo Central Hospital. The surgery department was most heavily affected, suggesting occupational risk. Isoniazid preventive therapy initiation was high and just over half completed therapy. An interferon gamma release assay was useful to discern LTBI from false positives among those with lower quantitative tuberculin skin test results.

Safety and Efficacy of Transjugular Liver Biopsy in Patients with Left Lobe-Only Liver Transplants.

PURPOSE: To evaluate efficacy and safety of transjugular liver biopsy (TJLB) via the left hepatic vein in patients with left lobe-only liver transplants (LLOTs). MATERIALS AND METHODS: Retrospective review revealed 43 TJLBs performed in 26 patients with LLOTs (mean age 51.3 y; range, 18-73 y) between January 2009 and June 2016 at a single institution. A comparison group of 44 randomly selected TJLBs performed in 37 orthotopic whole liver transplant (OWLT) recipients (mean age 57.6 y; range, 35-74 y) during the same time period was evaluated. Patient demographics, type and age of transplant, technical success, adequacy of samples, number of portal tracts obtained, pathologic diagnosis, and complication rate were reviewed. RESULTS: Technical success was achieved in 98% (42/43) of LLOT procedures. TJLB failed in 1 patient with LLOT, in whom no patent hepatic veins were identified. Technical success was achieved in 100% (44/44) in the OWLT group. Mean (SD) number of needle passes was 4.12 (1.25) in the LLOT group vs 3.95 (1.28) in the OWLT group (P = .54). Mean (SD) specimen length was 1.16 (0.75) cm in the LLOT group vs 1.19 (0.58) cm in the OWLT group (P = .78). Mean (SD) number of portal tracts obtained in the LLOT group was 10.7 (5.26) vs 12.3 (4.68) in the OWLT group (P = .17). No major complications were observed in either group. CONCLUSIONS: TJLB in adult patients with LLOTs appears safe and feasible, with favorable rates of technical success and adequacy of sampling.

Integrative detection and analysis of structural variation in cancer genomes.

Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.

Phosphoglycerate dehydrogenase inhibition induces p-mTOR-independent autophagy and promotes multilineage differentiation in embryonal carcinoma stem-like cells.

Cancer cells with a less differentiated stem-like phenotype are more resistant to therapeutic manipulations than their differentiated counterparts, and are considered as one of the main causes of cancer persistence and relapse. As such, induction of differentiation in cancer stem-like cells (CSLCs) has emerged as an alternative strategy to enhance the efficacy of anticancer therapies. CSLCs are metabolically distinct from differentiated cells, and any aberration from the intrinsic metabolic state can induce differentiation of CSLCs. Therefore, metabolism-related molecular targets, with a capacity to promote differentiation within CSLCs, are of therapeutic importance. Here, we demonstrate that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme catalyzing the synthesis of amino acid serine, is important for maintaining the poorly differentiated, stem-like state of CSLCs. Our data shows that PHGDH deficiency impairs the tumorsphere formation capacity in embryonal carcinoma stem-like cells (ECSLCs), breast cancer stem-like cells (BCSLCs) and patient-derived brain tumor-initiating cells (BTICs), which is accompanied by the reduced expression of characteristic stemness-promoting factors, such as Oct4, Nanog, Sox-2, and Bmi-1. Mechanistically, PHGDH deficiency in ECSLCs promotes differentiation to various lineages via degradation of Oct4 and by increasing the stability of differentiation marker ß3-tubulin. Furthermore, PHGDH inhibition promotes p-mTOR independent but Beclin-1-dependent autophagy, independent of apoptosis. When studied in combination, the inhibition of both PHGDH and p-mTOR in ECSLCs causes further augmentation of autophagy, and additionally promotes apoptosis, demonstrating the clinical applicability of PHGDH-based manipulations in cancer therapies. Recapitulating these in vitro findings in CSLC models, the intratumoral PHGDH expression in patient-derived tumors is positively correlated with the mRNA levels of stemness factors, especially Oct4, and cancer patients co-expressing high levels of PHGDH and Oct4 display significantly lower survival than those with low PHGDH/Oct4 co-expression. Altogether, this study identifies a clinically-relevant role for PHGDH in the regulation of stemness-differentiation axis within CSLCs.