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Tissue regeneration is a process by which the remaining cells of an injured organ regrow to offset the missed cells. This field is relatively a new discipline that has been a focus of intense research by clinicians, surgeons, and scientists for decades. It constitutes the cornerstone of tissue engineering, creation of artificial organs, and generation and utilization of therapeutic stem cells to undergo transformation to different types of mature cells. Many medical experts, scientists, biologists, and bioengineers have dedicated their efforts to deeply comprehend the process of liver regeneration, striving for harnessing it to invent new therapies for liver failure. Liver regeneration after partial hepatectomy in rodents has been extensively studied by researchers for many years. It is divided into three important distinctive phases including (a) Initiation or priming phase which includes an overexpression of specific genes to prepare the liver cells for replication, (b) Proliferation phase in which the liver cells undergo a series of cycles of cell division and expansion and finally, (c) termination phase which acts as brake to stop the regenerative process and prevent the liver tissue overgrowth. These events are well controlled by cytokines, growth factors, and signaling pathways. In this review, we describe the function, embryology, and anatomy of human liver, discuss the molecular basis of liver regeneration, elucidate the hepatocyte and cholangiocyte lineages mediating this process, explain the role of hepatic progenitor cells and elaborate the developmental signaling pathways and regulatory molecules required to procure a complete restoration of hepatic lobule. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Signaling Pathways > Global Signaling Mechanisms Gene Expression and Transcriptional Hierarchies > Cellular Differentiation

Proton MRS (1H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good‐quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi‐adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

Abstract Aims Left atrial (LA) function is impaired in heart failure with preserved ejection fraction (HFpEF) and predicts disease severity and risk of adverse outcome. We sought to evaluate whether LA strain could enhance diagnosis of HFpEF. Methods and results Consecutive patients with unexplained exertional dyspnoea and image quality suitable for measuring LA strain underwent invasive cardiopulmonary exercise testing to ascertain the presence of HFpEF or non-cardiac causes of dyspnoea (NCD). LA reservoir strain was measured in all patients, while LA conduit and booster strain were measured in patients with sinus rhythm. LA strain was measurable in 363 of 378 examinations (96.5%; HFpEF: 238, NCD: 125). LA reservoir strain (29 ± 16% vs. 40 ± 13%, P < 0.0001) and conduit strain (18 ± 10% vs. 22 ± 10%, P = 0.0001) were significantly impaired in HFpEF compared to NCD. Of all echocardiographic indices, LA reservoir strain best discriminated HFpEF from NCD [area under the curve (AUC) 0.719, P < 0.0001], outperforming E/e' (AUC difference +0.117, P < 0.0001), LA enlargement (+0.090, P = 0.001), tricuspid regurgitation velocity > 2.8 m/s (+0.082, P = 0.0085), left ventricular hypertrophy (+0.0159, P < 0.0001) and left ventricular global longitudinal strain (+0.0198, P < 0.0001). Indexing LA reservoir strain to estimated LA pressure (E/e') as a surrogate for LA compliance further improved diagnostic performance (AUC 0.772, P < 0.0001; +0.053 compared to LA reservoir strain alone, P = 0.003). Conclusion Left atrial reservoir strain may provide enhanced diagnostic accuracy beyond conventional echocardiographic measures to discriminate HFpEF from NCD. Further study is required to verify the diagnostic utility of LA strain.

Background: The patient/caregiver experience during CAR-T therapy is stressful, overwhelming, terrifying, and often a patient’s last treatment option. The Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery Innovation and Design team has worked with the CAR-T therapy clinical team to develop a patient experience that provides patients with a sense of caring, supportive environment, timely knowledge, and realistic expectations. Using a human-centered design approach, the Innovation and Design team worked with patients and caregivers to understand latent and unspoken needs in order to develop an ideal CAR-T therapy patient journey. Methods: With qualitative interviewing techniques, patient observation, and low fidelity experimentation, 21 patients/caregiver pairs were interviewed throughout their CAR-T therapy experience in 2018. Patients were interviewed at several touch points as well as encouraged to reach out to the Innovation and Design team at any point with reflections on their experiences. Patients were recruited as they began their evaluation phase for CAR-T therapy. The interviews were unscripted to allow for a breadth of discovery by not constraining the conversations to previously developed themes. As themes emerged from patient/caregiver interviews, artifacts and interventions were designed to alleviate pain points and improve the patient/caregiver experience. These artifacts and interventions were integrated into the clinical processes in real time and patient/caregivers were interviewed to understand the impact of these activities. Results: Several themes emerged from qualitative interviews with patients and caregivers. From the themes, interventions were developed. We were able to demonstrate a qualitative improvement in patient/caregiver experience through these interventions (Figure 1). Conclusions: Patients/caregivers undergoing CAR-T therapy have unique issues surrounding the logistics of care, emotional burden, and physical effects of treatment. We implemented processes to address these issues and observed a qualitative improvement via patient interviews/feedback. Ongoing work includes optimizing remote monitoring, digital platforms for patient education, and a quantitative study looking at patient reported outcomes (PROs) in such patients. To our knowledge, this is the first report for care delivery optimization in real-world practice for this new therapy.

Background and Purpose— Evidence suggests that atrial fibrillation (AF) is associated with increased risk of cognitive decline and dementia, even in the absence of stroke. White matter disease (WMD) is a potential mechanism linking AF to cognitive impairment. In this study, we explored the association between prevalent AF and WMD. Methods— We performed a cross-sectional analysis of participants attending the ARIC-NCS (Atherosclerosis Risk in Communities–Neurocognitive Study) in 2011 to 2013 who underwent brain magnetic resonance imaging. AF was ascertained from study visit electrocardiograms or prior hospitalization codes. Extent of WMD was defined by measures of white matter (WM) microstructural integrity and WM hyperintensity volume. Multivariable linear regression models were used to assess the association between AF and WMD. Results— Among 1899 participants (mean age, 76 years; 28% black; 60% women), 133 (7%) had prevalent AF. After multivariable adjustment, differences between participants with and without AF were −0.001 (95% CI, −0.006 to 0.004) for global WM fractional anisotropy, 0.031×10 −4 mm 2 /s (95% CI, −0.075 to 0.137) for global WM mean diffusivity, and 0.08 mm 3 (95% CI, −0.14 to 0.30) for WM hyperintensity volume. Conclusions— The results suggest that there is no association between prevalent AF and WMD.

PURPOSE The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA. METHODS We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease. RESULTS Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs. CONCLUSION This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.

PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m 2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

62 Background: We have previously reported that mutations in SPOP promote bromodomain and extra-terminal motif (BET) protein upregulation and BET inhibitor resistance in prostate cancer (Zhang et al., Nature Medicine 23(9):1055-1062, 2017). Other studies indicate that histone acetyltransferases (HATs) such as P300 are also upregulated in SPOP-mutated prostate cancer (Blattner et al., Cancer Cell 31: 436-451, 2017). Methods: We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. Results: We demonstrated that while prostate cancer cell lines expressing F133V, the most frequent SPOP mutant, are very resistant to both BET inhibitor JQ1 and CBP/P300 inhibitor CPI-637, they are very sensitive to simultaneous cotreatment with JQ1 and CPI-637. Similarly, we demonstrated that F133V mutant cells are also very sensitive to NEO2734. We established PDX and organoid models from a patient with prostate cancer expressing a novel SPOP mutation Q165P. Computer simulation analysis reveals that the Q165P mutation causes larger conformational fluctuation, indicating that the structure of Q165P is less stable than that of wild type SPOP. Accordingly, co-immunoprecipitation assay showed that Q165P mutation impaired the dimerization ability of SPOP. We further showed that the Q165P mutant organoid was very sensitive to NEO2734 in vitro and the Q165P mutant PDX was very sensitive to NEO2734 in mice. Conclusions: These PDX-based pre-clinical studies indicate that the inhibition of both BET and CBP-P300, either by co-administration of two agents, or by treatment with the dual inhibitor, NEO2734, is effective in SPOP-mutated prostate cancer. These data provide a strong rationale for the inclusion of patients with SPOP-mutated prostate cancer in clinical studies of NEO2734.