bluuebunny/crossref_metadata_2025 huggingface dataset:
Fasting Glucose of 6.1 mmol/L as a Possible Optimal Target for Type 2 Diabetic Patients with Insulin Glargine: A Randomized Clinical Trial
Authors: Yuan Lu , Li Fengfei , Zhou Yue , Sun Rui , Gao Gu , Zhang Qing , Tang Yajuan , Dai Lu , Wu Jindan , Ma Jianhua
Published: July 2021

To observe whether different insulin glargine titration algorithms based on fasting blood glucose (FBG) levels lead to different glycaemic variations (GVs) in type 2 diabetes (T2D) patients, a prospective, randomized, single-centre, comparative, three-arm parallel-group, open-label, treat-to-target, 24-week study was performed. A total of 71 uncontrolled T2D patients were recruited and randomized 1 : 3 : 3 into Groups 1, 2, and 3 (insulin titration goals of

FBG
≤
5.6

, ≤6.1, and ≤7.0) for this study. The initiated insulin glargine dose was recommended at 0.2 U/kg/day and was then titrated following the FBG target. Patients were subjected to two 3-day continuous glucose monitoring (CGM) at baseline and the endpoint, wherein the CGM data were analysed, and the study’s primary endpoint was the difference in 24 hrs mean amplitude of glycaemic excursion (MAGE) among the three groups. We observed that patients in the three groups had similar MAGE levels at the endpoint; however, Group 2 achieved a significant decrease in the MAGE level from baseline to the endpoint as compared to Groups 1 and 3 (all

p
<
0.05

). We also observed that these patients had significant glycated haemoglobin A1c (HbA1c) value improvements as compared to the other two groups (all

p
<
0.05

). Therefore, choosing an FBG level of 6.1 mmol/L as an insulin titration target provided significant GVs and HbA1c value improvements in T2D patients. Moreover, our data indicated that an FBG of 6.1 mmol/L could possibly be an insulin glargine titration target in T2D patients.
Fourier Transformation and Stability of a Differential Equation on

L

1

ℝ
Authors: Rezaei Hamid , Zafarasa Zahra , Karimi Lotfollah
Published: July 2021

In the present paper, by the Fourier transform, we show that every linear differential equation with constant coefficients of

n

-th order has a solution in

L

1

ℝ

which is infinitely differentiable in

ℝ
∖

0

. Moreover the Hyers–Ulam stability of such equations on

L

1

ℝ

is investigated.
Study on the Antitumor Effect and Glycolysis of Andrographolide in Anaplastic Thyroid Carcinoma
Authors: Yang Ke , Wu Ke , Feng Jianguo , Yutian Ling , Zhu Xin , Xu Dong
Published: July 2021

Objective. To investigate the antitumor effect of andrographolide on the ATC cell lines 8505C and CAL62 and to explore the possible mechanism of the effect. Methods. CCK8 and colony formation assays were performed to detect proliferation. Cell migration was tested by scratch assay. Annexin V/PI staining was used to detect cell apoptosis and cell cycle. Glucose and lactic acid kits were carried out to evaluate the glycolysis level after andrographolide treatment. Western blot was used to detect the changes in the apoptosis-related proteins and glycolysis-related enzymes in both 8505C and CAL62 cells. Results. Treatment with 60 μM andrographolide had significant effects on 8505C and CAL62, including inhibition of proliferation, inhibition of migration, arrest of the cell cycle, promotion of apoptosis, and inhibition of glycolysis. Conclusion. Andrographolide has an antitumor effect and can significantly affect glycolysis in ATC cells.
Adiponectin Treatment Attenuates Cerebral Ischemia‐Reperfusion Injury through HIF‐1α‐Mediated Antioxidation in Mice
Authors: Zhang Chan , Zhen Luming , Fang Zongping , Yu Liang , Zhang Yuanyuan , Wei Haidong , Jia Junfeng , Wang Shiquan
Published: July 2021

Adiponectin (ADPN) plays an important role in cerebral ischemia‐reperfusion injury. Although previous studies have confirmed that ADPN pretreatment has a protective effect on ischemic stroke, the therapeutic effect of ADPN on ischemic stroke and the underlying mechanism are still unclear. In order to clarify these questions, focal transient cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice and ADPN was administered for three times at 6 h, 24 h, and 48 h after reperfusion. Meanwhile, a virus‐delivered HIF‐1α siRNA was used before ADPN administration. The infarct volume, neurological score, cellular apoptosis, and oxidative stress were assessed at 72 h after reperfusion. The long‐term outcome of mice after stroke was recorded as well. The results indicated that ADPN treatment reduced the infarct volume (P = 0.032), neurological deficits (P = 0.047), cellular apoptosis (P = 0.041), and oxidative responses (P = 0.031) at 72 h after MCAO. Moreover, ADPN increased both the protein level and transcriptional activity of HIF‐1α as evidenced by the transcription levels of VEGF (P = 0.046) and EPO (P = 0.043) at 72 h after MCAO. However, knockdown of HIF‐1α partially reversed the antioxidant and treatment effect of ADPN after cerebral ischemia. In the observation of long‐term outcome after ADPN treatment, it demonstrated that ADPN not only prevented the cerebral atrophy (P = 0.031) and the neurological function decline (P = 0.048), but also promoted angiogenesis (P = 0.028) after stroke. In conclusion, our findings suggest that ADPN is effective in treatment of ischemic stroke which could be attributed to the increased antioxidant capacity regulated by HIF‐1α.
Combination of Xuesaitong and Aspirin Based on the Antiplatelet Effect and Gastrointestinal Injury: Study Protocol for a Randomized Controlled Noninferiority Trial
Authors: Zhu Bao-Chen , Xue Chun-Miao , Lang Rui , Weng Wei-Liang , Wang Xu-Jie , Lei Zhen-Zhen , Zhang Sha-Sha , Yang Wen-Hua , Zhang Wan-Tong , Hua Guo-Dong
Published: July 2021

Background. Aspirin is the first-line medication for prevention and treatment of coronary heart disease (CHD). However, long-term use of aspirin resulting in gastrointestinal mucosal injury and bleeding limits the regularity of medication. Xuesaitong is a marketed Chinese medicine contained main active component in Panax notoginseng saponins (PNS), which can significantly inhibit platelet aggregation in patients with CHD. Our previous studies have already showed that PNS could reduce the gastrointestinal mucosal injury caused by aspirin in preclinical study. However, there is a need for further clinical studies to evaluate synergy and attenuation effect of the combination. Methods. This trial is a prospectively planned, open-labeled, parallel-grouped, single-centered clinical trial. A total of eligible 480 participants will be randomly allocated into three groups: aspirin group, Xuesaitong group, and drug combination group at a ratio of 1 : 1 : 1. The primary outcome is the change of platelet aggregation rate and calprotectin activity. Secondary outcomes include PAC-1, P-selectin, P2Y12, I-FABP activity, and fecal occult blood. Discussion. The results of the study are expected to provide evidence of high methodological and reporting quality on the synergy function of Xuesaitong and aspirin upon the antiplatelet and anti-gastrointestinal injury effect for CHD. It also provides an experimental basis for clinical rational drug combination therapy. Trial Registration. This trial was registered in the Chinese Clinical Trail Registry, ChiCTR2000036311, on 22 August 2020, http://www.chictr.org.cn/edit.aspx?pid=58798&htm=4.
Hydrogeochemistry of Fluorine in Groundwater in Humid Mountainous Areas: A Case Study at Xingguo County, Southern China
Authors: Liu Jinhui , Wang Xinfeng , Xu Weidong , Song Mian , Gong Lei , Zhang Mengnan , Li Linbo , He Lishan
Published: July 2021

The understanding of F− concentration in groundwater in humid areas is limited although there are lots of research on high-fluoride groundwater in arid areas. In this paper, with controlling factors of F− concentrations in humid areas as the focus, 130 groundwater samples, obtained from four subsystems in Northwest Xingguo County, Jiangxi Province, China, were investigated to demonstrate the controlling factors of F− concentrations in humid areas. According to analytical results, the following hydrogeochemical characteristics of the fluorine in humid mountainous areas were determined: (1) F− concentration is positively correlated with total dissolved solids (TDS), Ca2+,

HCO

3
−

, and pH; (2) the groundwater features a high flow rate and low TDS; (3) the equilibrium constant of CaF2 is less than its solubility product constant, and the fluorine-bearing minerals in rocks are in a dissolved state; and (4) the dissolved fluoride-bearing minerals constitute the main sources of F− in the groundwater. Fluorine mainly comes from groundwater fluorine-bearing minerals in metamorphic rocks. Moreover, the low F− concentration in the groundwater mainly results from the fast flow rate of groundwater. Fluoride in groundwater has great potential hazards in humid areas.
Approximate Solution of Intuitionistic Fuzzy Differential Equations with the Linear Differential Operator by the Homotopy Analysis Method
Authors: Melliani S. , Belhallaj Z. , Elomari M. , Chadli L. S.
Published: July 2021

In this work, the purpose is to discuss the homotopy analysis method (HAM) for the use of intuitionistic fuzzy differential equations with the linear differential operator. Furthermore, a numerical example is presented to shed light on the capability of the present method, and the numerical results illustrated by adopting the homotopy perturbation method (HPM) are compared with the exact solution to ensure the validity of our outcomes.
Traditional Medicinal Vegetables in Northern Uganda: An Ethnobotanical Survey
Authors: Nakaziba Rebecca , Anyolitho Maxson Kenneth , Amanya Sharon Bright , Sesaazi Crispin Duncan , Byarugaba Frederick , Ogwal-Okeng Jasper , Alele Paul E.
Published: July 2021

Background. A wide range of indigenous vegetables grow in Uganda especially during rainy seasons but scarcely during droughts, except those that are commercially grown. Although a number of these vegetables have medicinal values, they have not been satisfactorily studied besides conservation. Therefore, we conducted a cross-sectional ethnobotanical survey in Northern Uganda in order to document traditional medicinal vegetables and their uses. Methods. Qualitative and quantitative approaches of data collection and analysis were employed using semistructured, interviewer-administered questionnaires as well as key informant interviews following international ethical codes. Fidelity levels and informant consensus factors were also calculated. Results. 13 traditional vegetables belonging to 10 families were reported to serve as folk medicines. The most dominant families were Fabaceae (23.08%) and Solanaceae (15.38%). The most often used vegetables were Corchorus spp., Hibiscus spp., and Asystasiagangeticafor musculoskeletal (51%), gastrointestinal (34.3%), and malaria (31.8%). The vegetables were cultivated in the backyard and the leaves stewed for the different ailments. The informant consensus factor was the highest for Corchorus spp., in the treatment of joint pain/stiffness (0.92-1) while the highest fidelity level was (60.42%) for Amaranthus spp., in the management of anemia. Conclusions. Northern Uganda has numerous traditional vegetables with medicinal benefits. Diseases treated range from gastrointestinal to reproductive through musculoskeletal abnormalities. The community obtains vegetable leaves from the backyard and stews them regularly for the medicinal purposes with no specific dosage. Therefore, we recommend studies to verify in laboratory models the efficacy of these vegetables and standardize the dosages.
Understanding Impedance Response Characteristics of a Piezoelectric‐Based Smart Interface Subjected to Functional Degradations
Authors: Nguyen Ba-Phu , Tran Quang Hung , Nguyen Thanh-Truong , Pradhan Ananta Man Singh , Huynh Thanh-Canh
Published: July 2021

The functionality of piezoelectric devices is of significant importance in the electromechanical impedance (EMI)‐based structural health monitoring (SHM) and damage detection. Despite the previous work, the EMI response characteristics of a degraded piezoelectric‐based smart interface have not been sufficiently investigated due to the difficulty in making realistic functional defects via the experiment. To overcome this issue, we present a predictive simulation strategy to comprehensively investigate the EMI response characteristics of a smart interface subjected typical functional degradations. For that, a bolted steel girder connection is selected as a host structure to experimentally conduct EMI response measurement via the smart interface. Then, a finite element (FE) model corresponding to the experimental model is established and updated to reproduce the measured EMI response. By using the updated FE model, four common degradation types, including shear lag effect, transducer debonding, transducer breakage, and interface detaching are simulated and their effects on the EMI response are comprehensively analyzed. It is found that the interface detaching defect has significant impacts on the primary resonances of the EMI response and generates additional peaks with complex modal shapes. Also, the functional defects can result in distinctive EMI response characteristics, which are promising for assessing the functional condition of the smart interface.
Multilane Microscopic Modeling to Measure Mobility and Safety Consequences of Mixed Traffic in Freeway Weaving Sections
Authors: Seraj Mudasser , Qiu Tony Z.
Published: July 2021

Weaving sections are components of highway networks that introduce a heightened likelihood for bottlenecks and collisions. Automated vehicle technology could address this as it holds considerable promise for transportation mobility and safety improvements. However, the implications of combining automated vehicles (AuVs) with traditional human-driven vehicles (HuVs) in weaving freeway sections have not been quantitatively measured. To address this gap, this paper objectively experimented with bidirectional (i.e., longitudinal and lateral) motion dynamics in a microscopic modeling framework to measure the mobility and safety implications for mixed traffic movement in a freeway weaving section. Our research begins by establishing a multilane microscopic model for studied vehicle types (i.e., AuV and HuV) from model predictive control with the provision to form a CACC platoon of AuV vehicles. The proposed modeling framework was tested first with HuV only on a two-lane weaving section and validated using standardized macroscopic parameters from the Highway Capacity Manual. This model was then applied to incrementally expand the AuV share for varying inflow rates of traffic. Simulation results showed that the maximum flow rate through the weaving section was attained at a 65% AuV share. At the same time, steadiness in the average speed of traffic was experienced with increasing AuV share. The results also revealed that a 95% AuV share could reduce potential conflicts by 94.28%. Finally, the results of simulated scenarios were consolidated and scaled to report expected mobility and safety outcomes from the prevailing traffic state and the optimal AuV share for the current inflow rate in weaving sections.
Experimental Study on Lightweight Precast Composite Slab of High‐Titanium Heavy‐Slag Concrete
Authors: Sun Jinkun , Yi Man Li Rita , Jotikasthira Nuttapong , Li Kui , Zeng Liyun
Published: July 2021

Precast composite slabs are an essential component in concrete‐prefabricated buildings. At present, there are problems such as overweightedness and imperfect test for quality and structural performance of the precast floors, leading to restriction in the development of prefabricated buildings. In this study, by using industrial solid‐waste high‐titanium heavy slag as coarse and fine aggregates, with fly ash and silica fume for the partial substitution of the cement, we developed a green lightweight precast composite slab of high‐titanium heavy‐slag concrete (LPCSHTHSC) after adding shale ceramite as the light aggregate. By selecting the weight and the strength of LPCSHTHSC as the technical control indexes, we performed an orthogonal test of lightweight proportions. Through a comprehensive analysis of the compressive strength, splitting tensile strength, density, and an economic consideration, the optimal proportion was determined as follows: water‐to‐binder ratio of 0.43, mixing amount of the fly ash of 4%, mixing amount of the silica fume of 8%, mixing amount of the water‐reducing agent of 0.5%, sand ratio of 35%, and cement at the strength grade of 42.5. Next, the bending performance test was conducted on LPCSHTHSC. According to the results, the LPCSHTHSC exhibited excellent mechanical performance, and its ultimate bearing capacity far exceeded the designed value. The ultimate bearing capacity calculated using the plastic hinge wire method differed slightly from the test value, suggesting the applicability of the proposed method to the calculation of the ultimate bearing capacity. Finally, the finite element analysis results of LPCSHTHSC were consistent with the actual bending mechanical performance test results, which proved both the accuracy and the reliability of the present finite element analysis based on the plastic damage constitutive model. The present study can provide an insightful theoretical and test foundation for the lightweight application of high‐titanium heavy‐slag concrete in other prefabricated components.
Comparable Efficacy and Safety of Teriflunomide versus Dimethyl Fumarate for the Treatment of Relapsing-Remitting Multiple Sclerosis
Authors: Nehzat Nasim , Mirmosayyeb Omid , Barzegar Mahdi , Vosoughi Reza , Fazeli Erfane , Shaygannejad Vahid
Published: July 2021

Background. The aim of this observational study is to investigate the efficacy and safety of two approved oral disease-modifying therapies (DMTs) in patients with remitting-relapsing multiple sclerosis (RRMS): dimethyl fumarate (DMF) vs. teriflunomide (TRF). Methods. A total of 159 RRMS patients (82 on TRF and 77 on DMF) were included. The expanded disability status scale (EDSS), confirmed disability improvement (CDI), confirmed disability progression (CDP), and annualized relapse rate (ARR) were evaluated for the two-year period prior to enrollment in our study. The drug-associated adverse effects (AEs) were recorded. We conducted propensity matching score to compare the efficacy between TRF and DMF. Results. After matching for the confounders, TRF- and DMF-treated groups were not different in terms of EDSS (

P

value = 0.54), CDI (

P

value = 0.80), CDP (

P

value = 0.39), and ARR (

P

value >0.05). TRF discontinuation occurred in 2 patients (2.43%) due to mediastinitis and liver dysfunction, while a patient (1.29%) discontinued DMF due to depression. Incidence rate of AEs in the TRF-treated group was 81.4%: hair thinning (hair loss) (62.9%), nail loss (20.9%), and elevated aminotransferase (14.8%) were the most common AEs; in DMF-treated patients, AEs were 88.2% with predominance of flushing (73.2%), pruritus (16.9%), and abdominal pain (16.9%). Conclusion. Based on our findings, DMF is as efficacious and safe as TRF for the treatment of RRMS in our Iranian study population. Multicentric studies need to corroborate these findings in other populations.
Refractory Spontaneous Bacterial Empyema in Cirrhotic Patient
Authors: Chow Erica , Khiatah Bashar , Frugoli Amanda
Published: July 2021

Spontaneous bacterial empyema (SBEM), also called spontaneous bacterial pleuritis, is an infection of the pleural space that arises in the setting of cirrhosis and, by definition, the absence of pneumonia. It is likely underdiagnosed as its symptoms are nonspecific and it lacks standardized diagnostic and therapeutic recommendations. SBEM represents a distinct complication of hepatic hydrothorax with different pathogenesis, presentation, and treatment strategy from those of empyema secondary to pneumonia. Surprisingly, nearly 40% of episodes of spontaneous empyema are not associated with spontaneous bacterial peritonitis. Although SBEM is amenable to prompt antibiotic therapy, it has a high rate of mortality and morbidity. A high clinical suspicion is crucial for patient survival and timely initiation of appropriate antibiotics. Increased understanding, recognition, and standardization of treatment would help alleviate the relatively high burden of SBEM. In this case vignette, we provide a review of the relevant literature, and we describe a rare case of SBEM in a patient with a history of alcohol-associated liver cirrhosis and prior episode of spontaneous bacterial peritonitis (SBP). SBEM was diagnosed with thoracentesis and analysis of the aspirate, and he was treated with ceftriaxone with resolution of his presenting abdominal pain and leukocytosis.
The Synergistic Effect of TRPV1 on Oxidative Stress-Induced Autophagy and Apoptosis in Microglia
Authors: Huang Tingting , Lin Yao , Pang Qiongyi , Shen Weimin , Chen Xiang , Tu Fengxia
Published: July 2021

Stroke mostly including ischemic stroke is the second leading mortality and disability worldwide. Oxidative stress injury occurred during ischemic stroke treatment generally. A high amount of reactive oxygen species (ROS) is involved in oxidative stress induction. Transient receptor potential vanilloid 1 (TRPV1) has been shown to regulate oxidative stress and apoptosis in microglia; however, the detailed mechanisms remain unclear. We aimed to explore whether autophagy-regulated oxidative stress and apoptosis are associated with TRPV1. The model of oxygen and glucose deprivation (OGD/R) in microglia was established. The siRNA of Atg5 and inhibitors and agonists of both autophagy and TRPV1 were involved in our study. Autophagy-related markers Atg5, LC3II/LC3I, and Beclin-1 were measured, and the autophagosome was observed under a transmission electron microscope (TEM). Caspase 3 was detected using ELISA. ROS and JC-1 were detected using flow cytometry. Apoptosis was observed by TUNEL. The results indicated that oxidative stress-induced injury and apoptosis may be impeded by the increasing autophagy, and TRPV1 inhibition could suppress the OGD/R-induced autophagy of microglia. However, the effect of TRPV1’s inhibitor on oxidative stress and apoptosis was not obvious when the autophagy was blocked. These findings suggested that TRPV1 may exhibit antioxidative and antiapoptosis effect on OGD/R-induced microglia. However, the experimental results do not fully demonstrate that the TRPV1-mediated antioxidative and antiapoptosis effect is through the affecting autophagy entirely.
Wound Healing Activities of Hydromethanolic Crude Extract and Solvent Fractions of Bersama abyssinica Leaves in Mice
Authors: Taddese Solome Melkamu , Gurji Tiruzer Bekele , Abdulwuhab Mohammedbrhan , Aragaw Tezera Jemere
Published: July 2021

Background. Bersama abyssinica leaves are traditionally used for management of wounds in several communities of Ethiopia, despite no scientifically approved studies done on wound healing. Our study planned to work out the wound healing effects of B. abyssinica leaves extract in mice. Methods. B. abyssinica leaves were extracted with 80% hydromethanol and fractioned with chloroform, hexane, and water. The acute dermal toxicity of the crude extract was evaluated in mice. The crude extract formulated at 5% and 10% w/w ointment was investigated in excision, incision, and burn wound models and solvent fractions in the excision model using simple ointment (negative control) and nitrofurazone 0.2% w/v (positive control). We evaluated histopathological analysis, wound contraction rate, complete epithelialization period, and skin durability. One-way ANOVA followed by the post hoc Tukey HSD test with IBM SPSS software version 23.0 was used for data analysis, and

p

 < 0.05 was considered statistically significant. Results. Hydromethanolic crude extract produced 5% (99.5%) and 10% (100%) wound contraction on the 16th day of the treatment and 5% (18.8) and 10% (28.2) percent reduction in the epithelization period on the excision wound healing model. Hydromethanolic crude extract produced 5% (47.5) and 10% (61.17) percent durability on the incision wound healing model. Hydromethanolic crude extract produced 5% (99.82%) and 10% (100%) wound contraction on the 20th day of treatment and 5% (13%) and 10% (21.7%) reduction in the epithelization period on the burn wound healing model. The chloroform fraction produced 5% (90.17%) and 10% (91.01%), hexane fraction produced 5% (85.81%) and 10% (86.78%), and aqueous fraction produced 5% (99.17%) and 10% (99.38%) wound contraction on the 14th day of the treatment and 5% (18.8) and 10% (28.2) percent reduction in the epithelization period on the excision wound healing model. Both hydromethanolic crude extract and solvent fractions at 5% and 10% (w/w) were significant (

p

 < 0.001) compared with negative control. Conclusion. The results of this study showed that both 5% w/w and 10% w/w of 80% hydromethanolic crude extract and solvent fractions of B. abyssinica leaves have wound healing effects.
[Retracted] RUNX3 Expression Level Is Correlated with the Clinical and Pathological Characteristics in Endometrial Cancer: A Systematic Review and Meta‐analysis
Authors: Liu Zhen , Hong Zhi-pan , Xi Shu-xue
Published: July 2021

Human Runt‐associated transcription factor 3 (RUNX3) plays an important role in the development and progression of endometrial cancer (EC). However, the clinical and pathological significance of RUNX3 in EC needs to be further studied. In order to clarify the clinical and pathological significance of RUNX3, a systematic review and meta‐analysis was conducted in EC patients. Keywords RUNX3, endometrial cancer, and uterine cancer were searched in Cochrane Library, Web of Knowledge, PubMed, CBM, MEDLINE, and Chinese CNKI database for data up to Dec 31, 2018. References, abstracts, and meeting proceedings were manually searched in supplementary. Outcomes were various clinical and pathological features. The two reviewers performed the literature searching, data extracting, and method assessing independently. Meta‐analysis was performed by RevMan5.3.0. A total of 563 EC patients were enrolled from eight studies. Meta‐analysis results showed that the expression of RUNX3 has significant differences in these comparisons: lymph node (LN) metastasis vs. non‐LN metastasis (P = 0.26), EC tissues vs. normal tissues (P < 0.00001), clinical stages I/II vs. II/IV (P < 0.00001), muscular infiltration < 1/2 vs. muscular infiltration ≥ 1/2 (P < 0.00001), and G1 vs. G2/G3 (P < 0.00001). The decreasing expression of RUNX3 is associated with poor TNM stage and muscular infiltration. It is indicated that RUNX3 was involved in the suppression effect of EC. However, further multicenter randomized controlled trials are needed considering the small sample size of the included trials.
Mevalonate Blockade in Cancer Cells Triggers CLEC9A+ Dendritic Cell-Mediated Antitumor Immunity
Authors: Xu Feifei , Wang Zining , Zhang Hongxia , Chen Jiemin , Wang Xiaojuan , Cui Lei , Xie Chunyuan , Li Mengyun , Wang Fang , Zhou Penghui , Liu Jinyun , Huang Peng , Xia Xiaodong , Xia Xiaojun
Published: July 2021

Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)–mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells. MVA pathway blockade or Rac1 knockdown in tumor cells induced CD8+ T-cell-mediated antitumor immunity in immunocompetent mice but not in Batf3−/− mice lacking CLEC9A+ dendritic cells. These findings demonstrate tumor MVA metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton, illustrating a new immune surveillance mechanism by which dendritic cells monitor tumor metabolic dysregulation and providing insight into how MVA pathway inhibition may potentiate anticancer immunity.

Significance:

These findings suggest that mevalonate blockade in cancer cells disrupts Rac1 prenylation to increase recognition and cross-presentation by conventional dendritic cells, suggesting this axis as a potential target for cancer immunotherapy.
Hypothermia Is a Potential New Therapy for a Subset of Tumors with Mutant p53
Authors: Hu Wenwei , Feng Zhaohui
Published: July 2021

The tumor suppressor p53 gene is mutated in approximately 50% of all human tumors. Many tumor-associated mutant p53 proteins misfold into a common, denatured conformation and accumulate to high levels in human tumors. In such tumors, these mutant forms of p53 provide a “gain of function” to promote tumor progression. Therefore, targeting mutant p53 has become an attractive approach for cancer therapy. In this issue, the study by Lu and colleagues supports the premise that certain forms of mutant p53 are temperature sensitive in conformation; these forms of p53 are mutant in conformation at physiologic temperature, but can refold into a normal, or “wild-type” conformation at lower temperature (32°C to 34°C). Notably, these temperature-sensitive mutants account for up to 7.5% of all human tumors that carry mutant p53, so this fraction of patients is estimated to be quite significant. Results from this study show that employing therapeutic hypothermia to reduce the core temperature of mice bearing tumors with these temperature-sensitive mutant forms of p53 (ts mutant p53) causes ts mutant p53 to switch to a wild-type conformation in tumors, inhibiting tumor growth. Moreover, combining hypothermia with chemotherapy leads to durable remission of such tumors, with no obvious toxicity to normal tissues.

See related article by Lu et al., p. 3905
Phase I Dose-Escalation Study of the Dual PI3K-mTORC1/2 Inhibitor Gedatolisib in Combination with Paclitaxel and Carboplatin in Patients with Advanced Solid Tumors
Authors: Colombo Ilaria , Genta Sofia , Martorana Federica , Guidi Monia , Frattini Milo , Samartzis Eleftherios Pierre , Brandt Simone , Gaggetta Sheila , Moser Laura , Pascale Mariarosa , Terrot Tatiana , Sessa Cristiana , Stathis Anastasios
Published: July 2021

Purpose:

This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel.

Patients and Methods:

Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression.

Results:

Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0–2). Median number of administered cycles was 6 (range, 2–16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2–G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results.

Conclusions:

Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.
Immune Profiling Mass Cytometry Assay Harmonization: Multicenter Experience from CIMAC-CIDC
Authors: Sahaf Bita , Pichavant Mina , Lee Brian H. , Duault Caroline , Thrash Emily M. , Davila Melanie , Fernandez Nicolas , Millerchip Karen , Bentebibel Salah-Eddine , Haymaker Cara , Sigal Natalia , Del Valle Diane M. , Ranasinghe Srinika , Fayle Sarah , Sanchez-Espiridion Beatriz , Zhang Jiexin , Bernatchez Chantale , Wu Catherine J. , Wistuba Ignacio I. , Kim-Schulze Seunghee , Gnjatic Sacha , Bendall Sean C. , Song Minkyung , Thurin Magdalena , Lee J. Jack , Maecker Holden T. , Rahman Adeeb
Published: July 2021

Purpose:

The Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) Network is supported by the NCI to identify biomarkers of response to cancer immunotherapies across clinical trials using state-of-the-art assays. A primary platform for CIMAC-CIDC studies is cytometry by time of flight (CyTOF), performed at all CIMAC laboratories. To ensure the ability to generate comparable CyTOF data across labs, a multistep cross-site harmonization effort was undertaken.

Experimental Design:

We first harmonized standard operating procedures (SOPs) across the CIMAC sites. Because of a new acquisition protocol comparing original narrow- or new wide-bore injector introduced by the vendor (Fluidigm), we also tested this protocol across sites before finalizing the harmonized SOP. We then performed cross-site assay harmonization experiments using five shared cryopreserved and one lyophilized internal control peripheral blood mononuclear cell (PBMC) with a shared lyophilized antibody cocktail consisting of 14 isotype-tagged antibodies previously validated, plus additional liquid antibodies. These reagents and samples were distributed to the CIMAC sites and the data were centrally analyzed by manual gating and automated methods (Astrolabe).

Results:

Average coefficients of variation (CV) across sites for each cell population were reported and compared with a previous multisite CyTOF study. We reached an intersite CV of under 20% for most cell subsets, very similar to a previously published study.

Conclusions:

These results establish the ability to reproduce CyTOF data across sites in multicenter clinical trials, and also highlight the importance of quality control procedures, such as the use of spike-in control samples, for tracking variability in this assay.
Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis
Authors: Bowen Charles M. , Walter Lewins , Borras Ester , Wu Wenhui , Ozcan Zuhal , Chang Kyle , Bommi Prashant V. , Taggart Melissa W. , Thirumurthi Selvi , Lynch Patrick M. , Reyes-Uribe Laura , Scheet Paul A. , Sinha Krishna M. , Vilar Eduardo
Published: July 2021

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP.

Prevention Relevance:

This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
Adiposity, Adulthood Weight Change, and Risk of Incident Hepatocellular Carcinoma
Authors: Simon Tracey G. , Kim Mi Na , Luo Xiao , Liu Xing , Yang Wanshui , Ma Yanan , Chong Dawn Q. , Fuchs Charles S. , Stampfer Meir , Giovannucci Edward L. , Chan Andrew T. , Zhang Xuehong
Published: July 2021

Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980–2012) and 48,026 men (1986–2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02–1.09 (Ptrend = 0.019), and 1.08; 95% CI = 1.06–1.10 (Ptrend = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01–1.08; Ptrend = 0.010), including after further adjusting for young-adult BMI (Ptrend = 0.010) and later-adult BMI (Ptrend = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5–<10 kg, 10–<20 kg, and ≥20 kg were, 1.40 (95% CI = 0.67–2.16), 2.09 (95% CI = 1.11–3.95), and 2.61 (95% CI = 1.42–5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk.

Prevention Relevance:

Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.
A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab
Authors: Adusumilli Prasad S. , Zauderer Marjorie G. , Rivière Isabelle , Solomon Stephen B. , Rusch Valerie W. , O'Cearbhaill Roisin E. , Zhu Amy , Cheema Waseem , Chintala Navin K. , Halton Elizabeth , Pineda John , Perez-Johnston Rocio , Tan Kay See , Daly Bobby , Araujo Filho Jose A. , Ngai Daniel , McGee Erin , Vincent Alain , Diamonte Claudia , Sauter Jennifer L. , Modi Shanu , Sikder Devanjan , Senechal Brigitte , Wang Xiuyan , Travis William D. , Gönen Mithat , Rudin Charles M. , Brentjens Renier J. , Jones David R. , Sadelain Michel
Published: July 2021

Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors.

Significance:

Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.

See related commentary by Aldea et al., p. 2674.

This article is highlighted in the In This Issue feature, p. 2659
An Apparently Balanced Complex Chromosome Rearrangement Involving Seven Breaks and Four Chromosomes in a Healthy Female and Segregation/Recombination in Her Affected Son
Authors: Campos Ana Eduarda , Rosenberg Carla , Krepischi Ana , França Marina , Lopes Vanessa , Nakano Viviane , Vertemati Tânia , Cochak Marcos , Migliavacca Michele , Milanezi Fernanda , Sousa Ana Cristina , Silva Juliana , Vieira Lígia , Monfredini Priscilla , Palumbo Ana Carolina , Fernandes Jonathas , Perrone Eduardo
Published: July 2021

Duplication of the distal 1q and 4p segments are both characterized by the presence of intellectual disability/neurodevelopmental delay and dysmorphisms. Here, we describe a male with a complex chromosome rearrangement (CCR) presenting with overlapping clinical findings between these 2 syndromes. In order to better characterize this CCR, classical karyotyping, FISH, and chromosomal microarray analysis were performed on material from the patient and his parents, which revealed an unbalanced karyotype with duplications at 1q41q43 and 4p15.2p14 in the proband. The rearrangements, which were derived from a maternal balanced karyotype, included an insertion of a segment from the long to the short arm of chromosome 1, a balanced translocation involving chromosomes 14 and 18, and an insertion of a segment from the short arm of chromosome 4 into the derived chromosome 14. This study aimed to better define the clinical history and prognosis of a patient with this rare category of chromosomal aberration. Our results suggest that the frequency of CCR in the general population may be underestimated; when balanced, they may not have a phenotypic effect. Moreover, they emphasize the need for cytogenetic techniques complementary to chromosomal microarray for proper genetic counseling.
Identification of Chromosome 17 Trisomy in a Cynomolgus Monkey (Macaca fascicularis) by Multicolor FISH Techniques
Authors: Kimura Aoi , Yahashi Satowa , Chatani Fumio , Tanabe Hideyuki
Published: July 2021

A female cynomolgus monkey (Macaca fascicularis) with facial features characteristic of Down syndrome showed abnormal behavior, unwariness toward humans, and poor concentration. The number of metaphase chromosomes in blood lymphocytes was examined and found to be 43, which indicated one extra chromosome to the normal diploid number (2n = 42). We then used Q-banding and multicolor FISH techniques to identify the extra chromosome. The results revealed an additional chromosome 17, with no other chromosomal rearrangements, such as translocations. Since no mosaicism or heterozygous variant chromosomes were observed, full trisomy 17 was assessed in this female cynomolgus monkey. Chromosome 17 corresponds to human chromosome 13, and human trisomy 13, known as Patau syndrome, results in severe clinical signs and, often, a short life span; however, this individual has reached an age of 10 years with only mild clinical signs. Although genomic differences exist between human and macaques, this individual’s case could help to reveal the pathological and genetic mechanisms of Patau syndrome.
Baseline Liver Function and Subsequent Outcomes in the Phase 3 REFLECT Study of Patients with Unresectable Hepatocellular Carcinoma
Authors: Vogel Arndt , Frenette Catherine , Sung Max , Daniele Bruno , Baron Ari , Chan Stephen L. , Blanc Jean Frédéric , Tamai Toshiyuki , Ren Min , Lim Howard J. , Palmer Daniel H. , Takami Yuko , Kudo Masatoshi
Published: July 2021

Introduction: Baseline liver function among patients starting treatment for unresectable hepatocellular carcinoma (uHCC) impacts survival and could impact efficacy outcomes and safety profiles of treatments. This post hoc analysis of the phase 3 REFLECT study examined the efficacy and safety outcomes for lenvatinib and for sorafenib in patients with uHCC, assessed by Child-Pugh score (CPS) and albumin-bilirubin (ALBI) grade. Methods: Efficacy and safety were assessed in patient cohorts from REFLECT according to study entry baseline ALBI grade and CPS. Results: Lenvatinib treatment generally provided survival benefits in all groups. Median overall survival (OS) among patients with an ALBI grade of 1 was consistently higher than among patients with an ALBI grade of 2 for both the lenvatinib and sorafenib arms (lenvatinib: 17.4 vs. 8.6 months; sorafenib: 14.6 vs. 7.7 months, respectively). Median OS among patients with a CPS of 5 was consistently higher than among patients with a CPS of 6 (lenvatinib: 15.3 vs. 9.4 months; sorafenib: 14.2 vs. 7.9 months, respectively). Progression-free survival and objective response rates for these ALBI grades and CPS demonstrated similar patterns. Among patients who received lenvatinib and experienced a treatment-related treatment-emergent adverse event leading to withdrawal, 6.6% had an ALBI grade of 1, while 13.3% had an ALBI grade of 2, and 7.9% had a CPS of 5, while 12.1% had a CPS of 6. Conclusions: Better liver function at baseline, as measured by ALBI grade or CPS, may be prognostic for better survival outcomes in patients with uHCC undergoing treatment with lenvatinib or sorafenib.
Modeling Manifest Huntington’s Disease Prevalence Using Diagnosed Incidence and Survival Time
Authors: Crowell Valerie , Houghton Richard , Tomar Akanksha , Fernandes Tricia , Squitieri Ferdinando
Published: July 2021

Introduction: Understanding the epidemiology of Huntington’s disease (HD) is key to assessing disease burden and the healthcare resources required to meet patients’ needs. We aimed to develop and validate a model to estimate the diagnosed prevalence of manifest HD by the Shoulson-Fahn stage. Methods: A literature review identified epidemiological data from Brazil, Canada, France, Germany, Italy, Spain, the UK, and the USA. Data on staging distribution at diagnosis, progression, and mortality were derived from Enroll-HD. Newly diagnosed patients with manifest HD were simulated by applying annual diagnosed incidence rates to the total population in each country, each year from 1950 onwards. The number of diagnosed prevalent patients from the previous year who remained in each stage was estimated in line with the probability of death or progression. Diagnosed prevalence in 2020 was estimated as the sum of simulated patients, from all the incident cohorts, still alive. Results: The model estimates that in 2020, there were 66,787 individuals diagnosed with HD in the 8 included countries, of whom 62–63% were in Shoulson-Fahn stages 1 and 2 (with less severely limited functional capacity than those in stages 3–5). Diagnosed prevalence is estimated to be 8.2–9.0 per 100,000 in the USA, Canada, and the 5 included European countries and 3.5 per 100,000 in Brazil. Conclusion: The modeled estimates generally accord with the previously published data. This analysis contributes to better understanding of the epidemiology of HD and highlights areas of uncertainty.