Narrative review of roles of astrocytes in subarachnoid hemorrhage.

Background and Objective: Astrocytes play an important role in healthy brain function, including the development and maintenance of blood-brain barrier (BBB), structural support, brain homeostasis, neurovascular coupling and secretion of neuroprotective factors. Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH) including neuroinflammation, glutamate toxicity, brain edema, vasospasm, BBB disruption, cortical spreading depolarization (SD). Methods: We searched PubMed up to 31 May, 2022 and evaluated the articles for screening and inclusion for subsequent systemic review. We found 198 articles with the searched terms. After exclusion based on the selection criteria, we selected 30 articles to start the systemic review. Key Content and Findings: We summarized the response of astrocytes induced by SAH. Astrocytes are critical for brain edema formation, BBB reconstruction and neuroprotection in the acute stage of SAH. Astrocytes clear extracellular glutamate by increasing the uptake of glutamate and Na+/K+ ATPase activity after SAH. Neurotrophic factors released by astrocytes contribute to neurological recovery after SAH. Meanwhile, Astrocytes also form glial scars which hinder axon regeneration, produce proinflammatory cytokines, free radicals, and neurotoxic molecules. Conclusions: Preclinical studies showed that therapeutic targeting the astrocytes response could have a beneficial effect in ameliorating neuronal injury and cognitive impairment after SAH. Clinical trials and preclinical animal studies are still urgently needed in order to determine where astrocytes stand in various pathway of brain damage and repair after SAH and, above all, to develop therapeutic approaches which benefit patient outcomes.

Qualitative Screening of Amphetamine- and Ketamine-Type Abuse Drugs in Urine Employing Dual Mode Extraction Column by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS).

This manuscript reported a fast and rapid qualitative screening method for abuse drugs in urine by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The scope of the abuse drugs under investigation included methamphetamine (MA), amphetamine (AMP), methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), paramethoxymethamphetamine (PMMA), ephedrine, pseudoephedrine, ketamine (KET), deschloroketamine (DCK), 2-fluorodeschloroketamine (2 F-DCK) and deschloro-N-ethylketamine (2-oxo-PCE). The method employed a dual mode extraction (DME) column as a novel clean-up method for the urine matrix. To an aliquot of 0.2 mL urine, internal standards (ISTDs) and 0.4 mL of acidified methanol were added. After vortex and centrifugation, the supernatant was passed through a DME column before LC-MS-MS analysis. Chromatographic separation was achieved with a C18 column by gradient elution. The limits of detection (LODs) for MA, AMP, MDMA, MDA and PMMA were 3 ng/mL, whereas those for ephedrine and pseudoephedrine were 10 ng/mL and those for KET, DCK, 2 F-DCK and 2-oxo-PCE were 1 ng/mL. The matrix effects ranged from -12% to 7% (%CV from 4% to 19%). This method is fit for the intended purpose for forensic toxicology, as well as for forensic analysis of drugs facilitating sexual assault and other criminal acts.

Safety for cervical corpectomy and diskectomy: univariate and multivariate analysis on predictors for prolonged ICU stay after anterior spinal fusion.

AIM: Cervical anterior spinal fusion (ASF) with corpectomy has risks of catastrophic acute complications such as airway obstruction requiring re-intubation. Our team has adopted a management plan for all cervical corpectomy patients to be admitted to the intensive care unit (ICU) after the operations for overnight observation. Some of these patients were kept intubated after the operations and transferred to the ICU. This study aims to review the outcome of this practice and to identify independent predictors associated with a prolonged ICU stay. METHODS: We reviewed consecutive patients with cervical ASF from January 2010 to June 2018. The primary outcome was the ICU length of stay. Univariate and multivariate analyses were conducted to identify independent risk factors associated with a prolonged ICU stay. In total, 103 patients had ASF during the study period. ICU length of stay for elective ASF was 1.01 day (SD 0.373 days) and was significantly shorter than that for emergency ASF (13.29 days, SD 12.57 days) (p < 0.001). 79.6% (82/103) of the ASF patients were extubated in the operating theatre after surgery. Significantly more corpectomy patients (33.3%) versus ACDF patients (15.1%) were kept intubated to the ICU after the operation (p = 0.037). None required reintubation in the ICU. 90.9% (80/88) of the elective ASF can be discharged from the ICU within 24 hours and only 3.41% (3/88) of the elective ASF had prolonged post-operative stay in the ICU (≥48 hours). RESULTS: For prolonged postoperative ICU stay (≥48 hours), ICU admission airway status of ASF patients who were either extubated in the OT or kept intubated to ICU had no significant association (p = 0.903). Univariate and multivariate analysis had identified emergency admissions (p = 0.043) and the presence of postoperative neurological deficits (p = 0.031) as independent predictors associated with a prolonged postoperative ICU stay. CONCLUSION: In conclusion, cervical corpectomy and ASF were safe with minimal acute complications.

Direct intralesional n-butyl-cyanoacrylate embolization for intractable vertebral hemangioma bleeding: a salvage technique. Illustrative case.

BACKGROUND: Surgical resection of vertebral hemangiomas in the setting of cord compression can be technically difficult and has the potential for life-threatening hemorrhage. The authors report a case of intraoperative direct intralesional n-butyl-cyanoacrylate embolization for intractable vertebral hemangioma bleeding. OBSERVATIONS: A 53-year-old woman presented for repeat surgery of a residual vertebral hemangioma after a previous debulking, laminectomy, and fixation that were without problems with bleeding. The second surgery was complicated by intractable hemorrhage. Bleeding was controlled with direct intralesional n-butyl-cyanoacrylate embolization after fluoroscopy without accompanying endovascular embolization. LESSONS: Aggressive vertebral hemangiomas should ideally be managed in centers where transarterial embolization is available. If such centers are not available or there is still intractable intraoperative bleeding despite preoperative embolization, direct intralesional embolization may be considered as a potential salvage technique.

Development of the SAFETEA Scores for Predicting Risks of Complications of Preventive Endovascular or Microneurosurgical Intracranial Aneurysm Occlusion.

OBJECTIVE: Preventive unruptured intracranial aneurysm occlusion can reduce the risk of subarachnoid hemorrhage, but both endovascular and microneurosurgical treatment carry a risk of serious complications. To improve individualized management decisions, we developed risk scores for complications of endovascular and microneurosurgical treatment based on easily retrievable patient, aneurysm, and treatment characteristics. METHODS: For this multicenter cohort study, we combined individual patient data from unruptured intracranial aneurysm patients ≥18 years undergoing preventive endovascular treatment (standard, balloon-assisted or stent-assisted coiling, Woven EndoBridge-device, or flow-diverting stent) or microneurosurgical clipping at one of 10 participating centers from three continents between 2000-2018. The primary outcome was death from any cause or clinical deterioration from neurological complications ≤30 days. We selected predictors based on previous knowledge about relevant risk factors and predictor performance and studied the association between predictors and complications with logistic regression. We assessed model performance with calibration plots and concordance (c) statistics. RESULTS: Of 1282 included patients, 94 (7.3%) had neurological symptoms that resolved <30 days, 140 (10.9%) had persisting neurological symptoms, and 6 died (0.5%)). At 30 days, 52 patients (4.1%) were dead or dependent. Predictors of procedural complications were: size of aneurysm, aneurysm location, familial subarachnoid hemorrhage, earlier atherosclerotic disease, treatment volume, endovascular modality (for endovascular treatment) or extra aneurysm configuration factors (for microneurosurgical treatment; branching artery from aneurysm neck or unfavorable dome-to-neck ratio), and age (acronym: SAFETEA). For endovascular treatment (n=752), the c-statistic was 0.72 (95%CI:0.67-0.77) and the absolute complication risk ranged from 3.2% (95%CI:1.6%-14.9%;≤1 point) to 33.1% (95%CI:25.4%-41.5%;≥6 points). For microneurosurgical treatment (n=530), the c-statistic was 0.72 (95%CI:0.67-0.77) and the complication risk ranged from 4.9% (95%CI:1.5%-14.9%;≤1 point) to 49.9% (95%CI:39.4%-60.6%;≥6 points). CONCLUSIONS: The SAFETEA risk scores for endovascular and microneurosurgical treatment are based on seven easily retrievable risk factors to predict the absolute risk of procedural complications in patients with unruptured intracranial aneurysms. The scores need external validation before the predicted risks can be properly used to support decision making in clinical practice.

How do terrestrial wildlife communities respond to small-scale Acacia plantations embedded in harvested tropical forest?

To offset the declining timber supply by shifting towards more sustainable forestry practices, industrial tree plantations are expanding in tropical production forests. The conversion of natural forests to tree plantation is generally associated with loss of biodiversity and shifts towards more generalist and disturbance tolerant communities, but effects of mixed-landuse landscapes integrating natural and plantation forests remain little understood. Using camera traps, we surveyed the medium-to-large bodied terrestrial wildlife community across two mixed-landuse forest management areas in Sarawak, Malaysia Borneo which include areas dedicated to logging of natural forests and adjacent planted Acacia forests. We analyzed data from a 25-wildlife species community using a Bayesian community occupancy model to assess species richness and species-specific occurrence responses to Acacia plantations at a broad scale, and to remote-sensed local habitat conditions within the different forest landuse types. All species were estimated to occur in both landuse types, but species-level percent area occupied and predicted average local species richness were slightly higher in the natural forest management areas compared to licensed planted forest management areas. Similarly, occupancy-based species diversity profiles and defaunation indices for both a full community and only threatened and endemic species suggested the diversity and occurrence were slightly higher in the natural forest management areas. At the local scale, forest quality was the most prominent predictor of species occurrence. These associations with forest quality varied among species but were predominantly positive. Our results highlight the ability of a mixed-landuse landscape with small-scale Acacia plantations embedded in natural forests to retain terrestrial wildlife communities while providing an alternate source of timber. Nonetheless, there was a tendency towards reduced biodiversity in planted forests, which would likely be more pronounced in plantations that are larger or embedded in a less natural matrix.

PHIL and Squid Embolization of Cerebral Arteriovenous Malformation: A Retrospective Case Series of 23 Patients.

Precipitating hydrophobic injectable liquid (PHIL; MicroVention, Aliso Viejo, CA, USA) and Squid (Balt, Irvine, CA, USA) are 2 newer liquid embolic agents used in endovascular embolization of cerebral arteriovenous malformation (AVM). This study aims to investigate and compare the effectiveness and safety profile of the 2 newer liquid embolic agents in the embolization of cerebral AVM. This is a retrospective study on all patients diagnosed with cerebral AVM undergoing endovascular embolization with liquid embolic agents PHIL and Squid admitted to the Division of Neurosurgery, Department of Surgery in Prince of Wales Hospital from January 2014 to June 2021. Twenty-three patients with cerebral AVM were treated with 34 sessions of endovascular embolization with either PHIL or Squid (17 sessions each) liquid embolic agents with a male to female ratio of 2.3:1 (male 16; female 7) and mean age of 44.6 (range, 12 to 67). The mean total nidus obliteration rate per session was 57% (range, 5% to 100%). Twenty-one patients (91.3%) received further embolization, stereotactic radiosurgery, or surgical excision after initial endovascular embolization. There were 2 morbidities (1 neurological and 1 non-neurological, 6%) and no mortalities (0%). All patients had static or improvement in modified Rankin Scale at 3 to 6 months at discharge. PHIL and Squid are effective and safe liquid embolic agents for endovascular embolization of cerebral AVM, achieving satisfactory nidal obliteration rates and patient functional outcomes.

ABC/2 formula for "bedside" postoperative pneumocephalus volume measurement.

BACKGROUND: Postoperative pneumocephalus is associated with a higher risk of recurrence of chronic subdural hematoma (cSDH). However, there is no verified simple way to measure the pneumocephalus volume at the bedside for daily clinical use. The ABC/2 method was shown to be a simple and reliable technique to estimate volumes of intracranial lesions, such as intracranial hematomas. This study aims to evaluate the accuracy of the ABC/2 formula in estimating volumes of pneumocephalus, as compared to the gold standard with computer-assisted volumetric analysis. METHODS: A total of 141 postoperative computed tomographic (CT) brain scans of cSDH patients with burr-hole drainage were analysed. Pneumocephalus volume was measured independently by both the ABC/2 formula and the computer-assisted volumetric measurement. For the computer-assisted measurement, the volume of the air was semiautomatically segmented and calculated by computer software. Linear regression was used to determine the correlation between the ABC/2 method and computer-assisted measurement. RESULTS: The postoperative pneumocephalus volume after bilateral burr-hole drainage was significantly larger than that of unilateral burr-hole drainage (29.34 ml versus 12.21 ml, p < 0.001). The estimated volumes by the formula ABC/2 significantly correlated to the volumes as measured by the computer-assisted volumetric technique, with r = 0.992 (p < 0.001). The Pearson correlation coefficient is very close to 1, which signifies a very strong positive correlation, and it is statistically significant. CONCLUSIONS: An excellent correlation is observed between the ABC/2 method and the computer-assisted measurement. This study verified that the ABC/2 method is an accurate and simple "bedside" technique to estimate pneumocephalus volume.

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury.

Over the last two decades, neurological researchers have uncovered many pathophysiological mechanisms associated with subarachnoid haemorrhage (SAH), with early brain injury and delayed cerebral ischaemia both contributing to morbidity and mortality. The current dilemma in SAH management inspired us to rethink the nature of the insult in SAH: sudden bleeding into the subarachnoid space and hypoxia due to disturbed cerebral circulation and increased intracranial pressure, generating exogenous stimuli and subsequent pathophysiological processes. Exogenous stimuli are defined as factors which the brain tissue is not normally exposed to when in the healthy state. Intersections of these initial pathogenic factors lead to secondary brain injury with related metabolic changes after SAH. Herein, we summarized the current understanding of efforts to monitor and analyse SAH-related metabolic changes to identify those precise pathophysiological processes and potential therapeutic strategies; in particular, we highlight the restoration of normal cerebrospinal fluid circulation and the normalization of brain-blood interface physiology to alleviate early brain injury and delayed neurological deterioration after SAH.

Univariate and Multivariable Analyses on Independent Predictors for Cervical Spinal Injury in Patients with Head Injury.

OBJECTIVE: This study aims to identify independent factors associated with cervical spinal injuries in head-injured patients. The extent of injuries to other body parts was assessed by the Abbreviated Injury Scale (AIS) and was included in the analysis. METHODS: Consecutive head-injured patients admitted via the emergency department from January 1, 2014 to December 31, 2016 were retrospectively reviewed. The inclusion criteria were head-injured patients with an Abbreviated Injury Scale (AIS) score ≥2 (i.e., head injuries with intracranial hematoma or skull fracture). Patients with minor head injuries with only scalp abrasions or superficial lacerations without significant intracranial injuries (i.e., head injury AIS score = 1) were excluded. The primary outcome was to identify independent predictors associated with cervical spinal injuries in these head-injured patients. Univariate and multivariable analyses were conducted. RESULTS: A total of 1105 patients were identified. Of these patients, 11.2% (n = 124) had cervical spinal injuries. Univariate and multivariable analyses identified male gender (P = 0.006), the presence of thoracic injury (including rib fracture, hemothorax, or pneumothorax) (P = 0.010), and hypotension with systolic blood pressure <90 mm Hg on admission (P = 0.009) as independent predictors for cervical spinal injury in head-injured patients. CONCLUSIONS: This study showed that about 1 in 10 patients with significant head injury had cervical spine injury, usually associated with fracture or dislocation. Male gender, the presence of thoracic injury, and hypotension on admission were independent risk factors associated with cervical spinal injuries.

Mitigation of SARS-CoV-2 transmission at a large public university.

In Fall 2020, universities saw extensive transmission of SARS-CoV-2 among their populations, threatening health of the university and surrounding communities, and viability of in-person instruction. Here we report a case study at the University of Illinois at Urbana-Champaign, where a multimodal "SHIELD: Target, Test, and Tell" program, with other non-pharmaceutical interventions, was employed to keep classrooms and laboratories open. The program included epidemiological modeling and surveillance, fast/frequent testing using a novel low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD, and digital tools for communication and compliance. In Fall 2020, we performed >1,000,000 covidSHIELD tests, positivity rates remained low, we had zero COVID-19-related hospitalizations or deaths amongst our university community, and mortality in the surrounding Champaign County was reduced more than 4-fold relative to expected. This case study shows that fast/frequent testing and other interventions mitigated transmission of SARS-CoV-2 at a large public university.

A Continuum Robotic Cannula With Tip Following Capability and Distal Dexterity for Intracerebral Hemorrhage Evacuation.

OBJECTIVE: This paper aims to investigate a new continuum robot design and its motion implementation methods appropriate for a minimally invasive intracerebral hemorrhage (ICH) evacuation. METHODS: We propose a continuum robotic cannula, consisting of a precurved body and a 2-degree-of-freedom (DoF) flexible tip, monolithically fabricated. Kinematic model with cable elongation model, and a dedicated design optimization and motion planning algorithm were developed to enable the follow-the-leader (FTL) motion of the cannula. A task-dependent Jacobian-based closed loop control was also designed to track the cannula motion during the insertion and its independent tip motion. RESULTS: Comprehensive experiments were conducted to verify the kinematic model and submillimeter motion coupling between the cannula precurved body and its flexible tip. The cannula was also capable of achieving FTL motion within around 2.5 mm shape deviation and control performance within submillimeter errors. It was finally demonstrated to be capable of the nonlinear insertion and tip manipulation in the brain phantom. CONCLUSION: The new cannula design, together with the proposed algorithms, provides the unique ability to access ICH in a nonlinear trajectory and dexterous tip motion. SIGNIFICANCE: These motion capabilities of the robot in such a slender form factor will lead to more complete ICH evacuation and reduced trauma to the healthy brain tissues.

Novel role of STAT3 in microglia-dependent neuroinflammation after experimental subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Signal transducer and activator of transcription 3 (STAT3) may contribute to the proinflammation in the central nervous system diseases by modulating the microglial responses. Thus, this study was intended to investigate the effect of STAT3 on microglia-dependent neuroinflammation and functional outcome after experimental subarachnoid haemorrhage (SAH). METHODS: The SAH model was established by endovascular perforation in the mouse. Real-time PCR (RtPCR) and western blot were used to examine the dynamic STAT3 signalling pathway responses after SAH. To clarify the role of the STAT3 signalling pathway in the microglia-dependent neuroinflammation after SAH, the microglia-specific STAT3 knockout (KO) mice were generated by the Cre-LoxP system. The neurological functions were assessed by Catwalk and Morris water maze tests. Neuronal loss after SAH was determined by immunohistochemistry staining. Microglial polarisation status after STAT3 KO was then examined by RtPCR and immunofluorescence. RESULTS: The STAT3 and Janus kinase-signal transducer 2 activated immediately with the upregulation and phosphorylation after SAH. Downstream factors and related mediators altered dynamically and accordingly. Microglial STAT3 deletion ameliorated the neurological impairment and alleviated the early neuronal loss after SAH. To investigate the underlying mechanism, we examined the microglial reaction after STAT3 KO. STAT3 deletion reversed the increase of microglia after SAH. Loss of STAT3 triggered the early morphological changes of microglia and primed microglia from M1 to M2 polarisation. Functionally, microglial STAT3 deletion suppressed the SAH-induced proinflammation and promoted the anti-inflammation in the early phase. CONCLUSIONS: STAT3 is closely related to the microglial polarisation transition and modulation of microglia-dependent neuroinflammation. Microglial STAT3 deletion improved neurological function and neuronal survival probably through promoting M2 polarisation and anti-inflammatory responses after SAH. STAT3 may serve as a promising therapeutic target to alleviate early brain injury after SAH.

Rescue therapy for vasospasm following aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis with machine learning.

OBJECTIVE: Rescue therapies have been recommended for patients with angiographic vasospasm (aVSP) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). However, there is little evidence from randomized clinical trials that these therapies are safe and effective. The primary aim of this study was to apply game theory-based methods in explainable machine learning (ML) and propensity score matching to determine if rescue therapy was associated with better 3-month outcomes following post-SAH aVSP and DCI. The authors also sought to use these explainable ML methods to identify patient populations that were more likely to receive rescue therapy and factors associated with better outcomes after rescue therapy. METHODS: Data for patients with aVSP or DCI after SAH were obtained from 8 clinical trials and 1 observational study in the Subarachnoid Hemorrhage International Trialists repository. Gradient boosting ML models were constructed for each patient to predict the probability of receiving rescue therapy and the 3-month Glasgow Outcome Scale (GOS) score. Favorable outcome was defined as a 3-month GOS score of 4 or 5. Shapley Additive Explanation (SHAP) values were calculated for each patient-derived model to quantify feature importance and interaction effects. Variables with high SHAP importance in predicting rescue therapy administration were used in a propensity score-matched analysis of rescue therapy and 3-month GOS scores. RESULTS: The authors identified 1532 patients with aVSP or DCI. Predictive, explainable ML models revealed that aneurysm characteristics and neurological complications, but not admission neurological scores, carried the highest relative importance rankings in predicting whether rescue therapy was administered. Younger age and absence of cerebral ischemia/infarction were invariably linked to better rescue outcomes, whereas the other important predictors of outcome varied by rescue type (interventional or noninterventional). In a propensity score-matched analysis guided by SHAP-based variable selection, rescue therapy was associated with higher odds of 3-month GOS scores of 4-5 (OR 1.63, 95% CI 1.22-2.17). CONCLUSIONS: Rescue therapy may increase the odds of good outcome in patients with aVSP or DCI after SAH. Given the strong association between cerebral ischemia/infarction and poor outcome, trials focusing on preventative or therapeutic interventions in these patients may be most able to demonstrate improvements in clinical outcomes. Insights developed from these models may be helpful for improving patient selection and trial design.

Microglia activation, classification and microglia-mediated neuroinflammatory modulators in subarachnoid hemorrhage.

Subarachnoid hemorrhage is a devastating disease with significant mortality and morbidity, despite advances in treating cerebral aneurysms. There has been recent progress in the intensive care management and monitoring of patients with subarachnoid hemorrhage, but the results remain unsatisfactory. Microglia, the resident immune cells of the brain, are increasingly recognized as playing a significant role in neurological diseases, including subarachnoid hemorrhage. In early brain injury following subarachnoid hemorrhage, microglial activation and neuroinflammation have been implicated in the development of disease complications and recovery. To understand the disease processes following subarachnoid hemorrhage, it is important to focus on the modulators of microglial activation and the pro-inflammatory/anti-inflammatory cytokines and chemokines. In this review, we summarize research on the modulators of microglia-mediated inflammation in subarachnoid hemorrhage, including transcriptome changes and the neuroinflammatory signaling pathways. We also describe the latest developments in single-cell transcriptomics for microglia and summarize advances that have been made in the transcriptome-based classification of microglia and the implications for microglial activation and neuroinflammation.

Establishment and characterization of meningioma patient-derived organoid.

Meningioma is a central nervous system tumor originated from arachnoid cells. 2D cell culture is widely used as a platform for tumor research as it enables us to culture cells in in vitro and a controlled environment. However, in 2D culture condition, 3D architecture of in vivo tumor mass is lost and phenotypic change may occur. Due to the drawbacks of 2D cell culture, organoid culture is seen as an alternative platform for disease modeling, drug testing and personalized medicine. The objective of this study was to establishing protocol for culturing cells from patient meningioma tissue in in vitro 3D environment. Eight meningiomas were collected for the 3D organoid culture. Cells of 5 meningioma tissues survived and proliferated. Under 3D culture condition, cell aggregates were formed and cytoplasmic processes linking the cell aggregates could be observed. In H&E staining, ovaloid cells and spindle cells were observed. Resembling cultured organoids observed under the light microscope, cell aggregates were also observed in the H&E staining. Epithelial Membrane Antigen (EMA) staining was positive. In 4 (80%) cultured organoids, low Ki67 index (≤6%) were measured. In one cultured organoid, a high Ki67 index (12.8%) was seen. The result of this study revealed the feasibility of culturing meningioma cells in in vitro 3D culture condition. Organoid technology showed its potential as an alternative platform for meningioma research.

Growth Inhibitory Efficacy of Chinese Herbs in a Cellular Model for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated with systemic toxicity, spontaneous and/or acquired tumor resistance and the emergence a of drug-resistant stem cell population. These limitations lead to advanced stage metastatic cancer. Current emphasis is on research directions that identify efficacious, naturally occurring agents representing an unmet need for testable therapeutic alternatives for therapy resistant breast cancer. Chinese herbs are widely used in traditional Chinese medicine in women for estrogen related health issues and also for integrative support for cancer treatment. This review discusses published evidence on a TNBC model for growth inhibitory effects of several mechanistically distinct nontoxic Chinese herbs, most of them nutritional in nature, and identifies susceptible pathways and potential molecular targets for their efficacy. Documented anti-proliferative and pro-apoptotic effects of these herbs are associated with downregulation of RB, RAS, PI3K, and AKT signaling, modulation of Bcl-2/BAX protein expressions and increased caspase activity. This review provides a proof of concept for Chinese herbs as testable alternatives for prevention/therapy of TNBC.