bluuebunny/crossref_metadata_2025 huggingface dataset:
Arbitrage Pricing with Heterogeneous Spatial Effects and Heteroscedastic Disturbances
Authors: Hu Jianhua , Ding Hao , Liu Xiaoqian
Published: January 2022

We develop a heterogeneous spatial arbit and regression coefficients, and heteroscedastic variances, and further establish identification of parameters and asymptotic normality of the conditional QML estimators under some mild conditions. We apply the proposed model to study a real data set of 11 eurozone stock index returns and extend the Fama–French five-factor model to regional stock indices, in which heterogeneous spatial effects and heteroscedastic disturbances are highly significant and they both play very important roles in explaining distinct endogenous effects and distinct risks of the 11 eurozone stock markets. Our empirical results reveal unique characteristics of each of 11 eurozone stock markets and their inner connections.
Extrapleural pneumonectomy for recurrent thymoma diagnosed after return of paraneoplastic Morvan syndrome
Authors: Banks Kian C , Hsu Diana S , Velotta Jeffrey B
Published: January 2022

A 50-year-old male with history of HIV, syphilis, paraneoplastic Morvan syndrome secondary to thymoma resected in 2013 presented recently with tachycardia, tremors, diarrhea, hyperhidrosis and bilateral lower extremity pain leading to the discovery of thymoma recurrence. He initially developed Morvan Syndrome after thymectomy in 2013 and gradually improved with negative anti-contactin-associated protein-like 2 antibody testing in 2017 and symptom resolution in 2018. Upon return of dysautonomia symptoms, subsequent imaging revealed widespread disease recurrence diffusely in the right lung parenchyma and pleura for which he underwent right extrapleural pneumonectomy. He was managed with low-dose prednisone perioperatively, but when his symptoms worsened, he was started on rituximab and methylprednisolone. Nearly 3 months from surgery, he died from urinary sepsis. This represents a unique case of recurrent paraneoplastic Morvan syndrome leading to the diagnosis of metastatic thymoma as well as the challenges of symptom control during the surgical management of the underlying disease.
Radial stellar populations, kinematics, and photometry of the cD galaxy NGC 6086 in Abell 2162
Authors: Pérez-Hernández E , Kemp S N , Ramirez-Siordia V H , Nigoche-Netro A
Published: January 2022

We present a full study of deep optical long-slit spectroscopy and deep broad-band photometry of NGC 6086. We cover up to at least 3re in spectroscopy and 5re in photometry (re ≈ 22 arcsec in our V-band photometry). The envelope first appears in the photometric profile around 23 arcsec, and the velocity dispersion, age, metallicity, and Mg2 indices all show changes starting at about this radius suggesting that we are seeing two separate structures (ellipsoid and envelope) with different properties in the data. We do not find the kinematically decoupled core reported in Carter et al. The velocity dispersion profile rises from 300 km s−1 in the centre to 600 km s−1 at 40 arcsec, a similar tendency to that previously observed in NGC 6166. Populations indicate a trend from old metal-rich stars to younger metal-poorer ones as the radius increases. Line-index analysis indicates that the α-element proportion is high at all radii and that the Mg2 index declines relatively steeply with radius. The photometry shows the extended envelope with a Sérsic index of 0.6 and flat colour gradients. Previous measurements of the velocity dispersion of the galaxies in the cluster A2162 are in the range 300–420 km s−1 for only around 40 member galaxies, but there appears to be a radial discontinuity in the distribution of galaxies and a flattish distribution in radial velocity, implying that the kinematics of this cluster requires further investigation.
Benign Metastasizing Leiomyomatosis to the Skin and Lungs, Intravenous Leiomyomatosis, and Leiomyomatosis Peritonealis Disseminata: A Series of Five Cases
Authors: Boavida Ferreira João , Cabrera Rafael , Santos Filipa , Relva Andreia , Vasques Hugo , Gomes António , Guimarães António , Moreira António
Published: January 2022

Benign metastasizing leiomyomatosis (BML) is a rare disease that typically occurs in women with a history of uterine leiomyomatosis. Benign metastasizing leiomyomatosis occurs more frequently in the lungs but may also develop in other organs and tissues. Other unusual variants of extra-uterine leiomyomatosis include intravenous leiomyomatosis (IVL) and leiomyomatosis peritonealis disseminata (LPD). In this article, three cases of BML are presented. One case, in a premenopausal woman, presented cutaneous metastases. We also present a case of IVL and a case of LPD, which occurred in postmenopausal women. Given the rarity of BML, IVL, and LPD, the authors reviewed the literature and herein discuss the implications for treatment in all five cases. Evidence for treating BML, IVL, and LPD is still scarce, and data available from our series and other small series seem to point to the patient’s hormonal status playing a fundamental part in the treatment plan. Furthermore, a collecting bag when performing excision of uterine leiomyomas may help avoid the potential spreading of leiomyomatosis. Hysterectomized patients with chronic cough, frequent respiratory infections, abdominal discomfort, right heart failure, or non-specific symptoms should be actively screened for BML, IVL, and LPD. Treatment should be individualized according to each patient’s hormonal status and desires.
Use of Single-Item Self-Rated Health Measure to Identify Frailty and Geriatric Assessment-Identified Impairments Among Older Adults with Cancer
Authors: Giri Smith , Mir Nabiel , Al-Obaidi Mustafa , Clark Deanna , Kenzik Kelly M , McDonald Andrew , Young-Smith Crystal , Paluri Ravi , Nandagopal Lakshmin , Gbolahan Olumide , Nyrop Kirsten A , Muss Hyman B , Pergolotti Mackenzi , Bhatia Smita , Williams Grant R
Published: January 2022

Background

Poor self-rated health (SRH) is a known predictor of frailty and mortality in the general population; however, its role among older adults with cancer is unknown. We evaluated the role of SRH as a potential screening tool to identify frailty and geriatric assessment (GA)-identified impairments.

Materials and Methods

Adults ≥60 years diagnosed with cancer in the UAB Cancer & Aging Resilience Evaluation (CARE) registry underwent a GA at the time of initial consultation. We measured SRH using a single-item from the Patient-Reported Outcomes Measurement Information System global health scale and dichotomized responses as poor (poor, fair) and good (good, very good, and excellent). We evaluated the diagnostic performance of SRH in measuring frailty, and GA impairment (≥2 deficits among a set of seven GA domains). We examined the impact of SRH with survival using a Cox model adjusting for confounders, exploring the mediating role of frailty.

Results

Six hundred and three older adults with cancer were included, with a median age of 69 years. Overall, 45% (n = 274) reported poor SRH. Poor SRH demonstrated high sensitivity and specificity for identifying frailty (85% and 78%, respectively) and GA impairment (75% and 78%, respectively). In a Cox regression model, poor SRH was associated with inferior survival (HR = 2.26; 95% CI 1.60-3.18) after adjusting for confounders; frailty mediated 69% of this observed relationship.

Conclusion

Self-rated health may be used as a screening tool to identify older adults with cancer with frailty and GA impairments. Poor SRH is associated with inferior survival, which is mediated by frailty.
Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review
Authors: Juat Damie J , Hachey Stephanie J , Billimek John , Del Rosario Michael P , Nelson Edward L , Hughes Christopher C W , Zell Jason A
Published: January 2022

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body’s own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.
Improved Survival of Young Adults with Cancer Following the Passage of the Affordable Care Act
Authors: Roth Michael , Berkman Amy , Andersen Clark R , Cuglievan Branko , Andrew Livingston J , Hildebrandt Michelle , Bleyer Archie
Published: January 2022

Background

Compared with their ensured counterparts, uninsured adolescents and young adults (AYAs) with cancer are more likely to present with advanced disease and have poor prognoses. The Patient Protection and Affordable Care Act (ACA), enacted in 2010, provided health care coverage to millions of uninsured young adults by allowing them to remain on their parents’ insurance until age 26 years (the Dependent Care Expansion, DCE). The impact of the expansion of insurance coverage on survival outcomes for young adults with cancer has not been assessed.

Participants

Utilizing the Surveillance, Epidemiology, and End Results database, we identified all patients aged 12-16 (younger-AYAs), 19-23 (middle-AYAs), and 26-30 (older-AYAs) who were diagnosed with cancer between 2006-2008 (pre-ACA) and 2011-2013 (post-ACA).

Methods

In this population-based cohort study, we used an accelerated failure time model to assess changes in survival rates before and after the enactment of the ACA DCE.

Results

Middle-AYAs ages 19-23 (thus eligible to remain on their parents’ insurance) experienced significantly increased 2-year survival after the enactment of the ACA DCE (survival time ratio 1.25, 95% confidence interval: 0.75-2.43, P = .029) and that did not occur in younger-AYAs (ages 12-16). Patients with sarcoma and acute myeloid leukemia accounted for the majority of improvement in survival. Middle-AYAs of hispanic ethnicity and those with low socioeconomic status experienced trends of improved survival after the ACA DCE was enacted.

Conclusion

Survival outcomes improved for young adults with cancer following the expansion of health insurance coverage. Efforts are needed to expand coverage for the millions of young adults who do not have health insurance.
The Impact of Breast Cancer Treatment Delays on Survival Among South African Women
Authors: Pumpalova Yoanna S , Ayeni Oluwatosin A , Chen Wenlong Carl , Buccimazza Ines , Cačala Sharon , Stopforth Laura W , Farrow Hayley A , Mapanga Witness , Nietz Sarah , Phakathi Boitumelo , Joffe Maureen , McCormack Valerie , Jacobson Judith S , Crew Katherine D , Neugut Alfred I , Ruff Paul , Cubasch Herbert , O’Neil Daniel S
Published: January 2022

Background

In high-income settings, delays from breast cancer (BC) diagnosis to initial treatment worsen overall survival (OS). We examined how time to BC treatment initiation (TTI) impacts OS in South Africa (SA).

Methods

We evaluated women enrolled in the South African BC and HIV Outcomes study between July 1, 2015 and June 30, 2019, selecting women with stages I-III BC who received surgery and chemotherapy. We constructed a linear regression model estimating the impact of sociodemographic and clinical factors on TTI and separate multivariable Cox proportional hazard models by first treatment (surgery and neoadjuvant chemotherapy (NAC)) assessing the effect of TTI (in 30-day increments) on OS.

Results

Of 1260 women, 45.6% had upfront surgery, 54.4% had NAC, and 19.5% initiated treatment >90 days after BC diagnosis. Compared to the surgery group, more women in the NAC group had stage III BC (34.8% vs 81.5%). Living further away from a hospital and having hormone receptor positive (vs negative) BC was associated with longer TTI (8 additional days per 100 km, P = .003 and 8 additional days, P = .01, respectively), while Ki67 proliferation index >20 and upfront surgery (vs NAC) was associated with shorter TTI (12 and 9 days earlier; P = .0001 and.007, respectively). Treatment initiation also differed among treating hospitals (P < .0001). Additional 30-day treatment delays were associated with worse survival in the surgery group (HR 1.11 [95%CI 1.003-1.22]), but not in the NAC group.

Conclusions

Delays in BC treatment initiation are common in SA public hospitals and are associated with worse survival among women treated with upfront surgery.
Three-Year Outcomes of a Phase II Study of Perioperative Capecitabine Plus Oxaliplatin Therapy for Clinical SS/SE N1-3 M0 Gastric Cancer (OGSG 1601)
Authors: Matsuyama Jin , Terazawa Tetsuji , Goto Masahiro , Kawabata Ryohei , Endo Shunji , Imano Motohiro , Fujita Shoichiro , Akamaru Yusuke , Taniguchi Hirokazu , Tatsumi Mitsutoshi , Lee Sang-Woong , Kawakami Hisato , Kurokawa Yukinori , Shimokawa Toshio , Sakai Daisuke , Kato Takeshi , Fujitani Kazumasa , Satoh Taroh
Published: January 2022

Background

We previously reported the good feasibility and favorable efficacy of perioperative capecitabine plus oxaliplatin (CapeOx) in patients (pts) with clinical T3(SS)/T4a(SE) N1-3 M0 gastric cancer (GC) in a phase II study in which the pathological response rate, the primary endpoint, of 54.1% was demonstrated. Here, we report 3-year follow-up data.

Methods

The eligibility criteria included clinical T3(SS)/T4a(SE) N1-3 M0 GC according to the Japanese Classification of Gastric Carcinoma-3rd English Edition (JCGC). Three cycles of neoadjuvant CapeOx (capecitabine, 2000mg/m2 for 14 days; oxaliplatin, 130mg/m2 on day 1, every 3 weeks) were administered, followed by 5 cycles of adjuvant CapeOx after D2 gastrectomy. Three-year overall survival and relapse-free survival are presented here, and analyzed by cohorts based on pathologic response rate (pRR).

Results

Thirty-seven pts were enrolled from July 2016 to May 2017, and fully evaluated for efficacy and toxicity. Thirty-three pts (89.2%) completed the planned three cycles of neoadjuvant CapeOx and underwent gastrectomy, with an R0 resection rate of 78.4% (n = 29). The overall survival (OS) rate and relapse-free survival (RFS) rate at 3 years was 83.8% (95% CI, 72.7-96.5%) and 73.0% (95% CI, 60.0-88.8%), respectively. Further, the 3-year OS rate in pts with pathological response of grade 1a (n = 13) and grade 1b or higher (n = 20) was 69.2% (95% CI: 48.2-99.5%) and 100.0%, respectively, based on JCGC. Pathological response rate was classified according to JCGC as follows: grade 0, the tumor was not affected; grade 1a, less than one-third of the tumor was affected; grade 1b, one to two thirds of the tumor was affected; grade 2, greater than or equal to two thirds was affected; and grade 3, no residual tumor. A pathological response was defined as grade 1b or greater.

Conclusion

Perioperative CapeOx showed good feasibility and favorable prognosis, especially in pts with pathological response of grade 1b or higher and was found to be useful in predicting prognosis. The data obtained using this novel approach warrant further investigation (Trial ID: UMIN000021641, jRCTs051180109).
Phase Ia/Ib Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors:  Safety, Efficacy, and Biomarkers
Authors: Wang Yakun , Liu Tianshu , Chen Gongyan , Gong Jifang , Bai Yuxian , Zhang Tao , Xu Nong , Liu Li , Xu Jianming , He Jianxing , Liu Yunpeng , Zhang Li , Jiang Da , Wang Mengzhao , Chang Jianhua , Li Wei , Bai Chunmei , Zhou Jinghong , Wang Jian , Ren Yongxin , Zhang Liya , Su Weiguo , Liu, Baorui , Shen Lin
Published: January 2022

Background

Savolitinib has shown good tolerability and preliminary efficacy, but efficacy biomarkers require investigation. The main purpose of this study was to confirm in Chinese patients the recommended phase II dose (RP2D) of savolitinib and to explore overall benefit in tumors bearing c-Met aberration.

Methods

This was an open-label, multi-center, 2-part phase I study. A starting dose of 600 mg QD was initiated in the escalation phase, utilizing a 3+3 design with repeated QD and BID dosing. In the dose expansion phase, we enrolled patients with gastric cancer and non–small cell lung cancer (NSCLC) with documented c-met aberration into 5 cohorts to further explore biomarkers. c-Met overexpression and amplification were assessed by immunohistochemistry and FISH, respectively.

Results

The safety analysis set included 85 patients. Only one dose-limiting toxicity (grade 3 fatigue) was reported in the 600 mg BID dosing group. The most frequent treatment-related adverse events were nausea (29.4%), vomiting (27.1%), and peripheral edema (21.2%). Notably, in gastric cancer, response was only observed in patients with MET amplification (copy number 9.7-18.4), with an objective response rate of 35.7% and a disease control rate of 64.3%. For patients with NSCLC bearing a MET exon 14 skipping mutation, obvious target lesion shrinkage was observed in 2 of 4 patients, although PR was not achieved.

Conclusion

The RP2D of savolitinib was established as 600 mg QD or 500 mg BID in Chinese patients. The promising response observed in patients with gastric cancer with c-met amplification and NSCLC with MET exon 14 skipping mutation warrants further investigation.

ClinicalTrials.gov Identifier

NCT0198555
Vincristine Sulfate Liposome Injection with Bendamustine and Rituximab as First-Line Therapy for B-Cell Lymphomas: A Phase I Study
Authors: Ollila Thomas , Butera James , Egan Pamela , Reagan John , Thomas Anthony , Yakirevich Inna , MacKinnon Kelsey , Margolis Jeannine , McMahon Jessica , Rosati Valerie , Olszewski Adam J
Published: January 2022

Background

We conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma.

Methods

Participants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph−) acute lymphoblastic leukemia (ALL).

Results

Among 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died.

Conclusion

Vincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.

Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.
Stimulating Calcium Handling in hiPSC-Derived Engineered Cardiac Tissues Enhances Force Production
Authors: Minor Alicia J , Coulombe Kareen L K
Published: January 2022

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have profound utility in generating functional human engineered cardiac tissues (ECT) for heart repair. However, the field at large is concerned about the relative immaturity of these hiPSC-CMs as we aim to develop clinically relevant models for regenerative therapy and drug testing. Herein, we develop a novel calcium (Ca2+) conditioning protocol that maintains ECTs in a physiological range of Ca2+ and assesses contractility in increasing calcium environments. Lactate-based selection served as a method to purify and shift the metabolic profile of hiPSC-CMs to evaluate the role of metabolism on Ca2+ sensitivity. After 2 weeks, we observe 2-fold greater peak twitch stress in high-Ca2+ conditioned ECTs, despite having lower stiffness and no change in Ca2+ sensitivity of twitch force. Interestingly, the force-calcium relationship reveals higher Ca2+ sensitivity in lactate conditioned tissues, suggesting that metabolic maturation alters mitochondrial Ca2+ buffering and regulation. Ca2+ sensitivity and force amplitude are not coupled, as lactate conditioned tissues produce force comparable to that of controls in high calcium environments. An upregulation of calcium handling protein gene expression likely contributes to the greater Ca2+ sensitivity in lactate conditioned hiPSC-CMs. Our findings support the use of physiological Ca2+ to enhance the functional maturation of excitation-contraction coupling in hiPSC-CMs and demonstrate that metabolic changes induced by lactate conditioning alter cardiomyocyte sensitivity to external Ca2+. These conditioning methods may be used to advance the development of engineered human cardiac tissue for translational applications in vitro and in vivo as a regenerative therapy.
Stem Cell-Induced Cell Motility: A Removable Obstacle on the Way to Safe Therapies?
Authors: Rosner Margit , Hengstschläger Markus
Published: January 2022

It is the hope of clinicians and patients alike that stem cell-based therapeutic products will increasingly become applicable remedies for many diseases and injuries. Whereas some multipotent stem cells are already routinely used in regenerative medicine, the efficacious and safe clinical translation of pluripotent stem cells is still hampered by their inherent immunogenicity and tumorigenicity. In addition, stem cells harbor the paracrine potential to affect the behavior of cells in their microenvironment. On the one hand, this property can mediate advantageous supportive effects on the overall therapeutic concept. However, in the last years, it became evident that both, multipotent and pluripotent stem cells, are capable of inducing adjacent cells to become motile. Not only in the context of tumor development but generally, deregulated mobilization and uncontrolled navigation of patient’s cells can have deleterious consequences for the therapeutic outcome. A more comprehensive understanding of this ubiquitous stem cell feature could allow its proper clinical handling and could thereby constitute an important building block for the further development of safe therapies.
Allogeneic Cell Combination Therapy Ameliorates Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction
Authors: Rieger Angela C , Tompkins Bryon A , Natsumeda Makoto , Florea Victoria , Banerjee Monisha N , Rodriguez Jose , Rosado Marcos , Porras Valeria , Valasaki Krystalenia , Takeuchi Lauro M , Collon Kevin , Desai Sohil , Bellio Michael A , Khan Aisha , Kashikar Nilesh D , Landin Ana Marie , Hardin Darrell V , Rodriguez Daniel A , Balkan Wayne , Hare Joshua M , Schulman Ivonne Hernandez
Published: January 2022

Background

Left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF.

Methods and Results

Yorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness.

Conclusions

Intra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.
Production of Mesenchymal Progenitor Cell-Derived Extracellular Vesicles in Suspension Bioreactors for Use in Articular Cartilage Repair
Authors: Phelps Jolene , Leonard Catherine , Shah Sophia , Krawetz Roman , Hart David A , Duncan Neil A , Sen Arindom
Published: January 2022

Mesenchymal progenitor cells (MPCs) have shown promise initiating articular cartilage repair, with benefits largely attributed to the trophic factors they secrete. These factors can be found in the conditioned medium (CM) collected from cell cultures, and it is believed that extracellular vesicles (EVs) within this CM are at least partially responsible for MPC therapeutic efficacy. This study aimed to examine the functionality of the EV fraction of CM compared to whole CM obtained from human adipose-derived MPCs in an in vivo murine cartilage defect model. Mice treated with whole CM or the EV fraction demonstrated an enhanced cartilage repair score and type II collagen deposition at the injury site compared to saline controls. We then developed a scalable bioprocess using stirred suspension bioreactors (SSBs) to generate clinically relevant quantities of MPC-EVs. Whereas static monolayer culture systems are simple to use and readily accessible, SSBs offer increased scalability and a more homogenous environment due to constant mixing. This study evaluated the biochemical and functional properties of MPCs and their EV fractions generated in static culture versus SSBs. Functionality was assessed using in vitro MPC chondrogenesis as an outcome measure. SSBs supported increased MPC expression of cartilage-specific genes, and EV fractions derived from both static and SSB culture systems upregulated type II collagen production by MPCs. These results suggest that SSBs are an effective platform for the generation of MPC-derived EVs with the potential to induce cartilage repair.
Definition and Characteristics of Mesenchymal Stromal Cells in Preclinical and Clinical Studies: A Scoping Review
Authors: Renesme Laurent , Pierro Maria , Cobey Kelly D , Mital Rhea , Nangle Kennedy , Shorr Risa , Lalu Manoj M , Thébaud Bernard
Published: January 2022

Mesenchymal stromal cells (MSCs) are widely used in preclinical and clinical research. Despite minimal criteria to define MSCs provided by the International Society for Cell and Gene Therapy (ISCT), concerns have been raised about inconsistent descriptions of cell products used. To address the question “How are MSCs currently defined and characterized?” we conducted a scoping review on original MSC preclinical and clinical studies published over a 3-month period. Selected studies identified from a systematic search of MEDLINE and Embase were categorized as follows: Clinical, Animal, Biology, or Biomaterial studies. Data were extracted from a randomly selected subsample of studies. We extracted information, including epidemiological characteristics of studies, study design, ISCT criteria, and MSC characterization and culture condition. A total of 1053 articles were included and among them, 318 articles were analyzed. Overall, 18% of the articles explicitly referred to the ISCT minimal criteria for MSC. MSC characteristics and culture conditions were inconstantly reported (eg, viability assay reported in only 18% of the articles). Only 20% of documents reported at least 1 functional assay. Clinical studies showed inconsistent completeness in reporting relevant information on the MSC characterization and cell manufacturing processes. These results suggest that further development and implementation of a consensus definition of MSCs and reporting guidelines are needed to enhance rigor, reproducibility, and transparency in MSC research.
Human Retinal Organoids Provide a Suitable Tool for Toxicological Investigations: A Comprehensive Validation Using Drugs and Compounds Affecting the Retina
Authors: Dorgau Birthe , Georgiou Maria , Chaudhary Alexander , Moya-Molina Marina , Collin Joseph , Queen Rachel , Hilgen Gerrit , Davey Tracey , Hewitt Philip , Schmitt Michael , Kustermann Stefan , Pognan Francois , Steel David H , Sernagor Evelyne , Armstrong Lyle , Lako Majlinda
Published: January 2022

Retinal drug toxicity screening is essential for the development of safe treatment strategies for a large number of diseases. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to the human retina and the ease of generation in large-scale formats. In this study, two hPSC cell lines were differentiated to retinal organoids, which comprised all key retinal cell types in multiple nuclear and synaptic layers. Single-cell RNA-Seq of retinal organoids indicated the maintenance of retinal ganglion cells and development of bipolar cells: both cell types segregated into several subtypes. Ketorolac, digoxin, thioridazine, sildenafil, ethanol, and methanol were selected as key compounds to screen on retinal organoids because of their well-known retinal toxicity profile described in the literature. Exposure of the hPSC-derived retinal organoids to digoxin, thioridazine, and sildenafil resulted in photoreceptor cell death, while digoxin and thioridazine additionally affected all other cell types, including Müller glia cells. All drug treatments caused activation of astrocytes, indicated by dendrites sprouting into neuroepithelium. The ability to respond to light was preserved in organoids although the number of responsive retinal ganglion cells decreased after drug exposure. These data indicate similar drug effects in organoids to those reported in in vivo models and/or in humans, thus providing the first robust experimental evidence of their suitability for toxicological studies.
Comparative Effects of Bone Marrow-derived Versus Umbilical Cord Tissue Mesenchymal Stem Cells in an Experimental Model of Bronchopulmonary Dysplasia
Authors: Benny Merline , Courchia Benjamin , Shrager Sebastian , Sharma Mayank , Chen Pingping , Duara Joanne , Valasaki Krystalenia , Bellio Michael A , Damianos Andreas , Huang Jian , Zambrano Ronald , Schmidt Augusto , Wu Shu , Velazquez Omaida C , Hare Joshua M , Khan Aisha , Young Karen C
Published: January 2022

Bronchopulmonary dysplasia (BPD) is a life-threatening condition in preterm infants with few effective therapies. Mesenchymal stem or stromal cells (MSCs) are a promising therapeutic strategy for BPD. The ideal MSC source for BPD prevention is however unknown. The objective of this study was to compare the regenerative effects of MSC obtained from bone marrow (BM) and umbilical cord tissue (UCT) in an experimental BPD model. In vitro, UCT-MSC demonstrated greater proliferation and expression of anti-inflammatory cytokines as compared to BM-MSC. Lung epithelial cells incubated with UCT-MSC conditioned media (CM) had better-wound healing following scratch injury. UCT-MSC CM and BM-MSC CM had similar pro-angiogenic effects on hyperoxia-exposed pulmonary microvascular endothelial cells. In vivo, newborn rats exposed to normoxia or hyperoxia (85% O2) from postnatal day (P) 1 to 21 were given intra-tracheal (IT) BM or UCT-MSC (1 × 106 cells/50 μL), or placebo (PL) on P3. Hyperoxia PL-treated rats had marked alveolar simplification, reduced lung vascular density, pulmonary vascular remodeling, and lung inflammation. In contrast, administration of both BM-MSC and UCT-MSC significantly improved alveolar structure, lung angiogenesis, pulmonary vascular remodeling, and lung inflammation. UCT-MSC hyperoxia-exposed rats however had greater improvement in some morphometric measures of alveolarization and less lung macrophage infiltration as compared to the BM-MSC-treated group. Together, these findings suggest that BM-MSC and UCT-MSC have significant lung regenerative effects in experimental BPD but UCT-MSC suppresses lung macrophage infiltration and promotes lung epithelial cell healing to a greater degree.
Differential Function and Maturation of Human Stem Cell-Derived Islets After Transplantation
Authors: Maxwell Kristina G , Kim Michelle H , Gale Sarah E , Millman Jeffrey R
Published: January 2022

Insulin-producing stem cell-derived islets (SC-islets) provide a virtually unlimited cell source for diabetes cell replacement therapy. While SC-islets are less functional when first differentiated in vitro compared to isolated cadaveric islets, transplantation into mice has been shown to increase their maturation. To understand the effects of transplantation on maturation and function of SC-islets, we examined the effects of cell dose, transplantation strategy, and diabetic state in immunocompromised mice. Transplantation of 2 and 5, but not 0.75 million SC-islet cells underneath the kidney capsule successfully reversed diabetes in mice with pre-existing diabetes. SQ and intramuscular injections failed to reverse diabetes at all doses and had undetectable expression of maturation markers, such as MAFA and FAM159B. Furthermore, SC-islets had similar function and maturation marker expression regardless of diabetic state. Our results illustrate that transplantation parameters are linked to SC-islet function and maturation, providing ideal mouse models for preclinical diabetes SC therapy research.
Lung Regeneration by Transplantation of Allogeneic Lung Progenitors Using a Safer Conditioning Regimen and Clinical-grade Reagents
Authors: Milman Krentsis Irit , Orgad Ran , Zheng Yangxi , Bachar Lustig Esther , Rosen Chava , Shezen Elias , Yadav Sandeep , Nathansohn Levi Bar , Assayag Miri , Berkman Neville , Karmouty Quintana Harry , Shoshan Einav , Blagdon Christa , Reisner Yair
Published: January 2022

Over the last decades, several studies demonstrated the possibility of lung regeneration through transplantation of various lung progenitor populations. Recently, we showed in mice that fetal or adult lung progenitors could potentially provide donor cells for transplantation, provided that the lung stem cell niche in the recipient is vacated of endogenous lung progenitors by adequate conditioning. Accordingly, marked lung regeneration could be attained following i.v. infusion of a single cell suspension of lung cells into recipient mice conditioned with naphthalene (NA) and 6Gy total body irradiation (TBI). As clinical translation of this approach requires the use of allogenic donors, we more recently developed a novel transplantation modality based on co-infusion of hematopoietic and lung progenitors from the same donor. Thus, by virtue of hematopoietic chimerism, which leads to immune tolerance toward donor antigens, the lung progenitors can be successfully engrafted without any need for post-transplant immune suppression. In the present study, we demonstrate that it is possible to replace NA in the conditioning regimen with Cyclophosphamide (CY), approved for the treatment of many diseases and that a lower dose of 2 GY TBI can successfully enable engraftment of donor-derived hematopoietic and lung progenitors when CY is administered in 2 doses after the stem cell infusion. Taken together, our results suggest a feasible and relatively safe protocol that could potentially be translated to clinical transplantation of lung progenitors across major MHC barriers in patients with terminal lung diseases.
Phase I/IIa Feasibility Trial of Autologous Quality- and Quantity-Cultured Peripheral Blood Mononuclear Cell Therapy for Non-Healing Extremity Ulcers
Authors: Tanaka Rica , Fujimura Satoshi , Kado Makiko , Fukuta Taro , Arita Kayo , Hirano-Ito Rie , Mita Tomoya , Watada Hirotaka , Kato Yoshiteru , Miyauchi Katsumi , Mizuno Hiroshi
Published: January 2022

Non-healing wounds are among the main causes of morbidity and mortality. We recently described a novel, serum-free ex vivo expansion system, the quantity and quality culture system (QQc), which uses peripheral blood mononuclear cells (PBMNCs) for effective and noninvasive regeneration of tissue and vasculature in murine and porcine models. In this prospective clinical study, we investigated the safety and efficacy of QQ-cultured peripheral blood mononuclear cell (MNC-QQ) therapy for chronic non-healing ischemic extremity wounds. Peripheral blood was collected from 9 patients with 10 chronic (>1 month) non-healing wounds (8 males, 1 female; 64-74 years) corresponding to ischemic extremity ulcers. PBMNCs were isolated and cultured using QQc. Within a 20-cm area surrounding the ulcer, 2 × 107 cells were injected under local anesthesia. Wound healing was monitored photometrically every 2 weeks. The primary endpoint was safety, whereas the secondary endpoint was efficacy at 12-week post-injection. All patients remained ambulant, and no deaths, other serious adverse events, or major amputations were observed for 12 weeks after cell transplantation. Six of the 10 cases showed complete wound closure with an average wound closure rate of 73.2% ± 40.1% at 12 weeks. MNC-QQ therapy increased vascular perfusion, skin perfusion pressure, and decreased pain intensity in all patients. These results indicate the feasibility and safety of MNC-QQ therapy in patients with chronic non-healing ischemic extremity wounds. As the therapy involves transplanting highly vasculogenic cells obtained from a small blood sample, it may be an effective and highly vasculogenic strategy for limb salvage.
T-cadherin Expressing Cells in the Stromal Vascular Fraction of Human Adipose Tissue: Role in Osteogenesis and Angiogenesis
Authors: Guerrero Julien , Dasen Boris , Frismantiene Agne , Pigeot Sebastien , Ismail Tarek , Schaefer Dirk J , Philippova Maria , Resink Therese J , Martin Ivan , Scherberich Arnaud
Published: January 2022

Cells of the stromal vascular fraction (SVF) of human adipose tissue have the capacity to generate osteogenic grafts with intrinsic vasculogenic properties. However, cultured adipose-derived stromal cells (ASCs), even after minimal monolayer expansion, lose osteogenic capacity in vivo. Communication between endothelial and stromal/mesenchymal cell lineages has been suggested to improve bone formation and vascularization by engineered tissues. Here, we investigated the specific role of a subpopulation of SVF cells positive for T-cadherin (T-cad), a putative endothelial marker. We found that maintenance during monolayer expansion of a T-cad-positive cell population, composed of endothelial lineage cells (ECs), is mandatory to preserve the osteogenic capacity of SVF cells in vivo and strongly supports their vasculogenic properties. Depletion of T-cad-positive cells from the SVF totally impaired bone formation in vivo and strongly reduced vascularization by SVF cells in association with decreased VEGF and Adiponectin expression. The osteogenic potential of T-cad-depleted SVF cells was fully rescued by co-culture with ECs from a human umbilical vein (HUVECs), constitutively expressing T-cad. Ectopic expression of T-cad in ASCs stimulated mineralization in vitro but failed to rescue osteogenic potential in vivo, indicating that the endothelial nature of the T-cad-positive cells is the key factor for induction of osteogenesis in engineered grafts based on SVF cells. This study demonstrates that crosstalk between stromal and T-cad expressing endothelial cells within adipose tissue critically regulates osteogenesis, with VEGF and adiponectin as associated molecular mediators.
Modulation of the Activity of Stem and Progenitor Cells by Immune Cells
Authors: Alshoubaki Yasmin K , Nayer Bhavana , Das Surojeet , Martino Mikaël M
Published: January 2022

Numerous components of the immune system, including inflammatory mediators, immune cells and cytokines, have a profound modulatory effect on the homeostatic regulation and regenerative activity of endogenous stem cells and progenitor cells. Thus, understanding how the immune system interacts with stem/progenitor cells could build the foundation to design novel and more effective regenerative therapies. Indeed, utilizing and controlling immune system components may be one of the most effective approaches to promote tissue regeneration. In this review, we first summarize the effects of various immune cell types on endogenous stem/progenitor cells, focusing on the tissue healing context. Then, we present interesting regenerative strategies that control or mimic the effect of immune components on stem/progenitor cells, in order to enhance the regenerative capacity of endogenous and transplanted stem cells. We highlight the potential clinical translation of such approaches for multiple tissues and organ systems, as these novel regenerative strategies could considerably improve or eventually substitute stem cell-based therapies. Overall, harnessing the power of the cross-talk between the immune system and stem/progenitor cells holds great potential for the development of novel and effective regenerative therapies.
Shipping and Logistics Considerations for Regenerative Medicine Therapies
Authors: Criswell Tracy , Swart Corné , Stoudemire Jana , Brockbank Kelvin , Floren Michael , Eaker Shannon , Hunsberger Joshua
Published: January 2022

Advances in regenerative medicine manufacturing continue to be a priority for achieving the full commercial potential of important breakthrough therapies. Equally important will be the establishment of distribution chains that support the transport of live cells and engineered tissues and organs resulting from these advanced biomanufacturing processes. The importance of a well-managed distribution chain for products requiring specialized handling procedures was highlighted during the COVID-19 pandemic and serves as a reminder of the critical role of logistics and distribution in the success of breakthrough therapies. This perspective article will provide insight into current practices and future considerations for creating global distribution chains that facilitate the successful deployment of regenerative medicine therapies to the vast number of patients that would benefit from them worldwide.
Current and Emerging Therapies for Limbal Stem Cell Deficiency
Authors: Elhusseiny Abdelrahman M , Soleimani Mohammad , Eleiwa Taher K , ElSheikh Reem H , Frank Charles R , Naderan Morteza , Yazdanpanah Ghasem , Rosenblatt Mark I , Djalilian Ali R
Published: January 2022

The corneal epithelium serves to protect the underlying cornea from the external environment and is essential for corneal transparency and optimal visual function. Regeneration of this epithelium is dependent on a population of stem cells residing in the basal layer of the limbus, the junction between the cornea and the sclera. The limbus provides the limbal epithelial stem cells (LESCs) with an optimal microenvironment, the limbal niche, which strictly regulates their proliferation and differentiation. Disturbances to the LESCs and/or their niche can lead to the pathologic condition known as limbal stem cell deficiency (LSCD) whereby the corneal epithelium is not generated effectively. This has deleterious effects on the corneal and visual function, due to impaired healing and secondary corneal opacification. In this concise review, we summarize the characteristics of LESCs and their niche, and present the current and future perspectives in the management of LSCD with an emphasis on restoring the function of the limbal niche.
The Influence of Cancer Stem Cells on the Risk of Relapse in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: A Prospective Cohort Study
Authors: Masciale Valentina , Banchelli Federico , Grisendi Giulia , D’Amico Roberto , Maiorana Antonino , Stefani Alessandro , Morandi Uliano , Stella Franco , Dominici Massimo , Aramini Beatrice
Published: January 2022

Purpose

Lung cancer relapse may be associated with the presence of a small population of cancer stem cells (CSCs) with unlimited proliferative potential. Our study assessed the relationship between CSCs and the relapse rate in patients harboring adenocarcinoma (ADL) and squamous cell carcinoma of the lung (SCCL).

Experimental design

This is an observational prospective cohort study (NCT04634630) assessing the influence of CSC frequency on relapse rate after major lung resection in 35 patients harboring early (I-II) (n = 21) and locally advanced (IIIA) (n = 14) ADL and SCCL. There was a 2-year enrollment period followed by a 1-year follow-up period. Surgical tumor specimens were processed, and CSCs were quantified by cytofluorimetric analysis.

Results

Cancer stem cells were expressed in all patients with a median of 3.1% of the primary cell culture. Primary analysis showed no influence of CSC frequency on the risk of relapse (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 0.85-1.30). At secondary analysis, patients with locally advanced disease with higher CSC frequency had an increased risk of relapse (HR = 1.26, 95% CI = 1.14-1.39), whereas this was not observed in early-stage patients (HR = 0.90, 95% CI = 0.65-1.25).

Conclusion

No association was found between CSC and relapse rates after major lung resection in patients harboring ACL and SCCL. However, in locally advanced-stage patients, a positive correlation was observed between CSC frequency and risk of relapse. These results indicate a need for further molecular investigations into the prognostic role of CSCs at different lung cancer stages.

Clinical Trial Registration

NCT04634630.
Constitutive High Expression of NOXA Sensitizes Human Embryonic Stem Cells for Rapid Cell Death
Authors: Basundra Richa , Kapoor Sahil , Hollville Emilie , Kiapour Nazanin , Beltran Lopez Adriana , Marie Melchiorre Nicole , Deshmukh Mohanish
Published: January 2022

Human embryonic stem (hES) cells are highly sensitive to apoptotic stimuli such as DNA damage, which allows for the rapid elimination of mutated cells during development. However, the mechanisms that maintain hES cells in the primed apoptotic state are not completely known. Key activators of apoptosis, the BH3-only proteins, are present at low levels in most cell types. In contrast, hES cells have constitutive high levels of the BH3-only protein, NOXA. We examined the importance of NOXA for enabling apoptosis in hES cells. hES cells deleted for NOXA showed remarkable protection against multiple apoptotic stimuli. NOXA was constitutively localized to the mitochondria, where it interacted with MCL1. Strikingly, inhibition of MCL1 in NOXA knockout cells was sufficient to sensitize these cells to DNA damage-induced cell death. Our study demonstrates that an essential function of constitutive high levels of NOXA in hES cells is to effectively antagonize MCL1 to permit rapid apoptosis.