bluuebunny/crossref_metadata_2025 huggingface dataset:
Proof Complexity for the Maximum Satisfiability Problem and its Use in SAT Refutations
Authors: Rollon Emma , Larrosa Javier
Published: February 2022

MaxSAT, the optimization version of the well-known SAT problem, has attracted a lot of research interest in the past decade. Motivated by the many important applications and inspired by the success of modern SAT solvers, researchers have developed many MaxSAT solvers. Since most research is algorithmic, its significance is mostly evaluated empirically. In this paper, we want to address MaxSAT from the more formal point of view of proof complexity. With that aim, we start providing basic definitions and proving some basic results. Then we analyse the effect of adding split and virtual, two original inference rules, to MaxSAT resolution. We show that each addition makes the resulting proof system stronger, even when virtual is restricted to empty clauses ($0$-virtual). We also analyse the power of our proof systems in the particular case of SAT refutations. We show that our strongest system, ResSV, is equivalent to circular and dual rail with split. We also analyse empirically some known gadget-based reformulations. Our results seem to indicate that the advantage of these three seemingly different systems over general resolution comes mainly from their ability of augmenting the original formula with hypothetical inconsistencies, as captured in a very simple way by the virtual rule.
Forbush decreases caused by paired interacting solar wind disturbances
Authors: Shlyk N S , Belov A V , Abunina M A , Abunin A A , Oleneva V A , Yanke V G
Published: February 2022

The paper discusses changes in various characteristics of the solar wind, interplanetary magnetic field, geomagnetic activity, and cosmic rays during the registration of paired interacting solar wind disturbances on the Earth using the data base of Forbush effects and interplanetary disturbances – FEID. The cases of pair interaction are considered for 1995–2020: (i) successive coronal mass ejections; (ii) coronal mass ejections and high-speed streams from coronal holes; (iii) successive high-speed streams from coronal holes. It is shown that for the first events from a pair, the times for reaching the maximum values of the interplanetary magnetic field and solar wind velocity are significantly reduced, and the amplitudes of the recorded Forbush decreases decline. It is also found that the presence of interaction enriches the second event at the expense of the resources of the first, increasing geomagnetic efficiency and the degree of cosmic ray modulation for the second event in comparison with isolated events, which is especially pronounced for a pair of interacting coronal mass ejections. The existence of the described effects can be explained by the observed increase in the interplanetary magnetic field magnitude in the second events due to the presence of interaction.
Secretion and uptake of copper via a small copper carrier in blood fluid
Authors: Gioilli B D , Kidane T Z , Fieten H , Tellez M , Dalphin M , Nguyen A , Nguyen K , Linder M C
Published: February 2022

Studies with Wilson disease model mice that accumulate excessive copper, due to a dysfunctional ATP7B “copper pump” resulting in decreased biliary excretion, showed that the compensatory increase in urinary copper loss was due to a small copper carrier (∼1 kDa) (SCC). We show here that SCC is also present in the blood plasma of normal and Wilson disease model mice and dogs, as determined by ultrafiltration and size exclusion chromatography (SEC). It is secreted by cultured hepatic and enterocytic cells, as determined by pretreatment with 67Cu nitrilotriacetate (NTA) or nonradioactive 5–10 μM Cu-NTA, and collecting and examining 3 kDa ultrafiltrates of the conditioned media, where a single major copper peak is detected by SEC. Four different cultured cell types exposed to the radiolabeled SCC all took up the 67Cu at various rates. Rates differed somewhat when uptake was from Cu-NTA. Uptake of SCC-67Cu was inhibited by excess nonradioactive Cu(I) or Ag(I) ions, suggesting competition for uptake by copper transporter 1 (CTR1). Knockout of CTR1 in fibroblasts reduced uptake rates by 60%, confirming its participation, but also involvement of other transporters. Inhibitors of endocytosis, or an excess of metal ions taken up by divalent metal transporter 1, did not decrease SCC-67Cu uptake. The results imply that SCC may play a significant role in copper transport and homeostasis, transferring copper particularly from the liver (but also intestinal cells) to other cells within the mammalian organism, as well as spilling excess into the urine in copper overload—as an alternative means of copper excretion.
Positive supercoiling favors transcription elongation through lac repressor-mediated DNA loops
Authors: Xu Wenxuan , Yan Yan , Artsimovitch Irina , Dunlap David , Finzi Laura
Published: February 2022

Some proteins, like the lac repressor (LacI), mediate long-range loops that alter DNA topology and create torsional barriers. During transcription, RNA polymerase generates supercoiling that may facilitate passage through such barriers. We monitored E. coli RNA polymerase progress along templates in conditions that prevented, or favored, 400 bp LacI-mediated DNA looping. Tethered particle motion measurements revealed that RNA polymerase paused longer at unlooped LacI obstacles or those barring entry to a loop than those barring exit from the loop. Enhanced dissociation of a LacI roadblock by the positive supercoiling generated ahead of a transcribing RNA polymerase within a torsion-constrained DNA loop may be responsible for this reduction in pause time. In support of this idea, RNA polymerase transcribed 6-fold more slowly through looped DNA and paused at LacI obstacles for 66% less time on positively supercoiled compared to relaxed templates, especially under increased tension (torque). Positive supercoiling propagating ahead of polymerase facilitated elongation along topologically complex, protein-coated templates.
G-quadruplex inducer/stabilizer pyridostatin targets SUB1 to promote cytotoxicity of a transplatinum complex
Authors: Hou Yinzhu , Gan Tieliang , Fang Tiantian , Zhao Yao , Luo Qun , Liu Xingkai , Qi Luyu , Zhang Yanyan , Jia Feifei , Han Juanjuan , Li Shumu , Wang Shijun , Wang Fuyi
Published: February 2022

Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and stabilizer, yet its target genes have remained unclear. Herein, applying MS proteomics strategy, we revealed PDS significantly downregulated 22 proteins but upregulated 16 proteins in HeLa cancer cells, of which the genes both contain a number of G4 potential sequences, implying that PDS regulation on gene expression is far more complicated than inducing/stabilizing G4 structures. The PDS-downregulated proteins consequently upregulated 6 proteins to activate cyclin and cell cycle regulation, suggesting that PDS itself is not a potential anticancer agent, at least toward HeLa cancer cells. Importantly, SUB1, which encodes human positive cofactor and DNA lesion sensor PC4, was downregulated by 4.76-fold. Further studies demonstrated that the downregulation of PC4 dramatically promoted the cytotoxicity of trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) toward HeLa cells to a similar level of cisplatin, contributable to retarding the repair of 1,3-trans-PtTz crosslinked DNA lesion mediated by PC4. These findings not only provide new insights into better understanding on the biological functions of PDS but also implicate a strategy for the rational design of novel multi-targeting platinum anticancer drugs via conjugation of PDS as a ligand to the coordination scaffold of transplatin for battling drug resistance to cisplatin.
Primary brain and other central nervous system tumors in the United States (2014-2018): A summary of the CBTRUS statistical report for clinicians
Authors: Low Justin T , Ostrom Quinn T , Cioffi Gino , Neff Corey , Waite Kristin A , Kruchko Carol , Barnholtz-Sloan Jill S
Published: February 2022

Background

The Central Brain Tumor Registry of the United States (CBTRUS) contains information on all primary brain and other central nervous system (CNS) tumors diagnosed in the United States (US). Here we summarize the 2021 CBTRUS annual statistical report for clinicians.

Methods

Incidence survival data are obtained from the Centers for Disease Control’s National Program of Cancer Registries (NPCR) and National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Survival data are obtained from NPCR. Mortality data are obtained from the National Vital Statistics System. Incidence and mortality rates are age-adjusted using the 2000 US population and presented per 100,000 population.

Results

An annual average of 86,355 cases of primary malignant and nonmalignant CNS tumors were diagnosed over the period 2014–2018, corresponding to an average annual age-adjusted incidence rate of 24.25. The most commonly occurring malignant tumor was glioblastoma (14.3%), and the most common predominately nonmalignant tumor was meningioma (39%). Over the 2014–2018 period, there were 16,606 annual average deaths due to malignant primary CNS tumors, corresponding to an average annual age-adjusted mortality rate of 4.43. In this report we detail key incidence, survival, and mortality statistics for major primary CNS tumor histologies, highlighting relevant differences by age, sex, and race.

Conclusions

This summary describes the most up to date population-based incidence of primary malignant and nonmalignant brain and other CNS tumors in the US, and mortality and survival for primary malignant tumors and aims to serve as a useful resource for clinicians.
Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride
Authors: Hu Yali , Tian Zi-You , Xiong Wei , Wang Dedao , Zhao Ruichi , Xie Yan , Song Yu-Qin , Zhu Jun , Lu Hua
Published: February 2022

The production of polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is usually conducted under stringent anhydrous conditions. The ROP of proline NCA (ProNCA) for the synthesis of poly-L-proline (PLP) is particularly challenging due to the premature product precipitation as polyproline type I helices, leading to slow reactions for up to one week, poor control of the molar mass and laborious workup. Here, we report the unexpected water-assisted controlled ROP of ProNCA, which affords well-defined PLP as polyproline II helices in 2–5 minutes and almost-quantitative yields. Experimental and theoretical studies together suggest the as-yet-unreported role of water in facilitating proton shift, which significantly lowers the energy barrier of the chain propagation. The scope of initiators can be expanded from hydrophobic amines to encompass hydrophilic amines and thiol-bearing nucleophiles, including complex biomacromolecules such as proteins. Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach. PLP modification not only preserves the biological activities of the native proteins, but also enhances their resistance to extreme conditions. Moreover, PLP modification extends the elimination half-life of asparaginase (ASNase) 18-fold and mitigates the immunogenicity of wt ASNase >250-fold (ASNase is a first-line anticancer drug for lymphoma treatment). This work provides a simple solution to a long-standing problem in PLP synthesis, and offers valuable guidance for the development of water-resistant ROP of other proline-like NCAs. The facile access to PLP can greatly boost the application potential of PLP-based functional materials for engineering industry enzymes and therapeutic proteins.
Impact of G-CSF Prophylaxis on Chemotherapy Dose-Intensity, Link Between Dose-Intensity and Survival in Patients with Metastatic Pancreatic Adenocarcinoma
Authors: Canton Clémence , Boussari Olayidé , Boulin Mathieu , Le Malicot Karine , Taieb Julien , Dahan Laetitia , Lopez Anthony , Lepage Come , Bachet Jean-Baptiste
Published: February 2022

Background

In metastatic pancreatic adenocarcinoma, few data are available on the use of granulocyte-colony stimulating factor (G-CSF) prophylaxis and its impact on dose-intensity (DI), or the link between DI and progression-free survival (PFS). This study assessed the impact of G-CSF prophylaxis on the DI received by patients and the relationship between full DI and PFS according to chemotherapy regimens.

Patients and Methods

Patients from three first-line randomized phase II clinical trials were included in this retrospective cohort. G-CSF prophylaxis groups were identified and balanced according to baseline characteristics using a propensity score. Patients were classified into 2 treatment groups (FOLFIRINOX vs FOLFIRI/nab-paclitaxel (NAB)). DI was a binary variable (full/reduced). Adverse events were defined using NCI-CTCAE v4.0.

Results

Of the 498 patients, 154 (31%) were in “prophylaxis” group; 179 (36%) were treated by FOLFIRINOX and 319 (64%) by FOLFIRI/NAB. In FOLFIRINOX group, G-CSF prophylaxis was significantly associated with a higher rate of full DI (OR, 5.07; 95% CI, 1.52-16.90; P < .01) while in FOLFIRI/NAB group, it was significantly associated with a lower rate of full DI (OR, 0.23; 95% CI, 0.06-0.83; P = .03). Full DI was associated with a non-significant increase in PFS (FOLFIRINOX group: HR 0.83; 95% CI, 0.59-1.16; P = .27; FOLFIRI/NAB group: HR 0.84; 95% CI, 0.63-1.11; P = .22).

Conclusion

Granulocyte-colony stimulating factor prophylaxis was associated with a higher rate of full DI with FOLFIRINOX. Full DI was associated with a non-significant increase in PFS. These results need to be confirmed prospectively.
Incidence, Clinical Characteristics, and Predictors of Cardiovascular Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors
Authors: Isawa Tsuyoshi , Toi Yukihiro , Sugawara Shunichi , Taguri Masataka , Toyoda Shigeru
Published: February 2022

Background

Cardiovascular immune-related adverse events (CV–irAEs) associated with immune checkpoint inhibitors (ICIs) may have been underreported given that most previous reports were retrospective. We aimed to evaluate the incidence, clinical characteristics, and predictors of CV–irAEs and determine the feasibility of serial cardiac monitoring using a combination of B-type natriuretic peptide, cardiac troponin T, and electrocardiogram for the prediction of future symptomatic (grade ≥2) CV–irAEs.

Materials and Methods

This was a prospective observational study that included 129 consecutive patients with non–small-cell lung cancer who received ICI monotherapy at a single center. Serial cardiac monitoring was performed during ICI monotherapy.

Results

A total of 35 (27%) patients developed any grade ≥1 CV–irAEs with a median time of onset of 72 (interquartile range 44-216) days after ICI treatment initiation. Multivariate Fine–Gray regression analysis showed that prior acute coronary syndrome (adjusted hazard ratio [HR] 3.15 (95% [CI], 2.03-4.91), prior heart failure hospitalization (adjusted HR 1.65 [95% CI, 1.17-2.33]), and achievement of disease control (adjusted HR 1.91, [95% CI, 1.16-3.14]) were significantly associated with grade ≥1 CV–irAEs. Serial cardiac monitoring revealed that patients with preceding grade 1 CV–irAEs were associated with a significantly higher risk of onset of grade ≥2 CV–irAEs compared with those without preceding grade 1 CV–irAEs (HR: 6.17 [95% CI, 2.97-12.83]).

Conclusion

CV–irAEs were more common than previously recognized and have several predictors. Moreover, serial cardiac monitoring may be feasible for the prediction of future grade ≥2 CV–irAEs.
Sustained defense response via volatile signaling and its epigenetic transcriptional regulation
Authors: Onosato Haruki , Fujimoto Genya , Higami Tomota , Sakamoto Takuya , Yamada Ayaka , Suzuki Takamasa , Ozawa Rika , Matsunaga Sachihiro , Seki Motoaki , Ueda Minoru , Sako Kaori , Galis Ivan , Arimura Gen-ichiro
Published: February 2022

Plants perceive volatiles emitted from herbivore-damaged neighboring plants to urgently adapt or prime their defense responses to prepare for forthcoming herbivores. Mechanistically, these volatiles can induce epigenetic regulation based on histone modifications that alter the transcriptional status of defense genes, but little is known about the underlying mechanisms. To understand the roles of such epigenetic regulation of plant volatile signaling, we explored the response of Arabidopsis (Arabidopsis thaliana) plants to the volatile β-ocimene. Defense traits of Arabidopsis plants toward larvae of Spodoptera litura were induced in response to β-ocimene, through enriched histone acetylation and elevated transcriptional levels of defense gene regulators, including ethylene response factor genes (ERF8 and ERF104) in leaves. The enhanced defense ability of the plants was maintained for 5 d but not over 10 d after exposure to β-ocimene, and this coincided with elevated expression of those ERFs in their leaves. An array of histone acetyltransferases, including HAC1, HAC5, and HAM1, were responsible for the induction and maintenance of the anti-herbivore property. HDA6, a histone deacetylase, played a role in the reverse histone remodeling. Collectively, our findings illuminate the role of epigenetic regulation in plant volatile signaling.
Implementing a Patrol-driven Intelligence Officer program: A Policing Innovation Trial
Authors: Bottema A Johannes , Rountree-Jackson Wendy , Telep Cody W
Published: February 2022

Intelligence-led policing focuses on using intelligence and analysis to reduce, address, and prevent crime or other forms of harm through a wide array of strategies. Traditionally, this has been associated with a top-down approach. A collaborative effort by the Phoenix Police Department and Arizona State University sought to take an innovative approach by introducing a patrol-driven programme: the Intelligence Officer (IO) Programme. This article utilizes data from the IO Programme to examine the importance of the police–university partnership in expanding the programme and the success of two critical areas of the programme: the training of patrol officers and their contribution to the successful application of intelligence. Generally, surveys demonstrate high receptivity to the basic and advanced IO Programme training. Daily logs and IO reports also indicate that the IO Programme has tangible benefits with great potential for success. The implications of these findings and potential avenues for research are discussed.
Physical Therapist Residency Competency-Based Education: Development of an Assessment Instrument
Authors: Harrington Kendra L , Teramoto Masaru , Black Lisa , Carey Helen , Hartley Greg , Yung Emmanuel , Osborne Jacqueline , Goldberg Penny , Tran Rachel Tabak , Hillegass Ellen
Published: February 2022

Objective

The objective of this study was to develop generic domains of competence (DoC) with associated competencies and milestones for physical therapist residency education. This work was intended to culminate in establishing validity evidence to support a competency-based assessment instrument that could be used by residency programs to evaluate resident achievement of the competencies, regardless of specialty area.

Methods

Employing the modified Delphi method, a residency education work group developed an evaluation instrument that included 7 DoC and 31 associated competencies with 6 milestones as rating scales for each competency. The instrument was distributed to mentors and residents in accredited physical therapist residency programs to establish validity evidence. Evaluations (measured by milestones) and demographics were collected at 3 time points (program entry, midterm, and final). Scores across these time points were compared using Kruskal-Wallis tests. Reliability was assessed with kappa statistics (interrater reliability) and alpha reliability coefficients (internal consistency). Construct validity was examined using confirmatory factor analysis via structural equation modeling.

Results

Overall, 237 mentors and 228 residents completed 824 evaluations (460 by mentors and 364 resident self-evaluations) across the time points. Scores significantly increased from entry through final time points. The interrater reliability of the associated behaviors ranged from moderate to substantial agreement (κ = 0.417–0.774). The internal consistency was high for all DoC at every time point (α reliability coefficients = .881–.955 for entry, .857–.925 for midterm, and .824–.902 for final). After confirmatory factor analysis with structural equation modeling was performed, a model that included 7 DoC and 20 associated competencies was proposed.

Conclusions

The residency assessment instrument developed demonstrates interrater reliability and validity evidence and therefore supports competency-based assessment of resident clinical performance across specialty areas. Additionally, the instrument aligns the physical therapy profession with other professions, such as medicine, dentistry, and pharmacy, that have transitioned to competency-based education.

Impact

This study outlines the benefits of moving to competency-based education for physical therapist residents, using a sound evaluation tool that evaluates residents across specialty areas. The instrument will allow for transition to competency-based education in physical therapist residency education programs.
Conversations that warm the heart: positive and negative links to the mental health challenges of the Covid-19 pandemic
Authors: Peterson Candida C
Published: February 2022

Background

Public-health precautions to curb Covid-19 (e.g. lockdowns) threaten mental health and emotional wellbeing, especially for today’s youngest adults. Their overuse of solitary, screen-mediated social media, plus underdeveloped in-person conversation skills, heighten their vulnerability to mental health problems such as loneliness, anxiety and depression.

Methods

To explore interconnections among variables such as social media use, empathic skills for in-person conversation and strategies for coping with Covid-19 anxiety, Australian 18- to 26-year-olds took several novel in-depth questionnaire measures that were purpose-built for the present research.

Results

Main findings were threefold: (i) Individuals who most frequently and wholeheartedly enjoyed live in-person conversations with friends suffered the most Covid-19 anxiety, worry and stress during periods of pandemic restriction. (ii) Empathic conversational skills were highest among those who conversed in-person (by phone or face-to-face) most often and were lowest for those who rarely did so and/or had little skill with in-person conversation. (iii) Those who gained the greatest relief from anxiety (e.g. about Covid-19) through solitary use of screen-based social media and games had the fewest empathic conversational skills.

Conclusions

Implications of these findings for suggesting possible future interventions to help young people cope with public health measures such as lockdowns and to foster community health and wellbeing are discussed.
Sirt1 Protects Subventricular Zone-Derived Neural Stem Cells from DNA Double-Strand Breaks and Contributes to Olfactory Function Maintenance in Aging Mice
Authors: Ren Jie , Wang Xianli , Dong Chuanming , Wang Guangming , Zhang Wenjun , Cai Chunhui , Qian Minxian , Yang Danjing , Ling Bin , Ning Ke , Mao Zhiyong , Liu Baohua , Wang Tinghua , Xiong Liuliu , Wang Wenyuan , Liang Aibin , Gao Zhengliang , Xu Jun
Published: February 2022

DNA damage is assumed to accumulate in stem cells over time and their ability to withstand this damage and maintain tissue homeostasis is the key determinant of aging. Nonetheless, relatively few studies have investigated whether DNA damage does indeed accumulate in stem cells and whether this contributes to stem cell aging and functional decline. Here, we found that, compared with young mice, DNA double-strand breaks (DSBs) are reduced in the subventricular zone (SVZ)-derived neural stem cells (NSCs) of aged mice, which was achieved partly through the adaptive upregulation of Sirt1 expression and non-homologous end joining (NHEJ)-mediated DNA repair. Sirt1 deficiency abolished this effect, leading to stem cell exhaustion, olfactory memory decline, and accelerated aging. The reduced DSBs and the upregulation of Sirt1 expression in SVZ-derived NSCs with age may represent a compensatory mechanism that evolved to protect stem cells from excessive DNA damage, as well as mitigate memory loss and other stresses during aging.
Active living-oriented zoning codes and cardiometabolic conditions across the lifespan
Authors: Zenk Shannon N , Pugach Oksana , Chriqui Jamie F , Wing Coady , Raymond Dorrie , Tarlov Elizabeth , Sheridan Bethany , Jones Kelly K , Slater Sandy J
Published: February 2022

Environments that make it easier for people to incorporate physical activity into their daily life may help to reduce high rates of cardiometabolic conditions. Local zoning codes are a policy and planning tool to create more walkable and bikeable environments. This study evaluated relationships between active living-oriented zoning code environments and cardiometabolic conditions (body mass index, hyperlipidemia, hypertension). The study used county identifiers to link electronic health record and other administrative data for a sample of patients utilizing primary care services between 2012 and 2016 with county-aggregated zoning code data and built environment data. The analytic sample included 7,441,991 patients living in 292 counties in 44 states. Latent class analysis was used to summarize municipal- and unincorporated county-level data on seven zoning provisions (e.g., sidewalks, trails, street connectivity, mixed land use), resulting in classes that differed in strength of the zoning provisions. Based on the probability of class membership, counties were categorized as one of four classes. Linear and logistic regression models estimated cross-sectional associations with each cardiometabolic condition. Models were fit separately for youth (aged 5–19), adults (aged 20–59), and older adults (aged 60+). Little evidence was found that body mass index in youth, adults, or older adults or the odds of hyperlipidemia or hypertension in adults or older adults differed according to the strength of active living-oriented zoning. More research is needed to identify the health impacts of zoning codes and whether alterations to these codes would improve population health over the long term.
Deep-sea discoveries
Authors: Przeslawski Rachel , Christenhusz Maarten J M
Published: February 2022

The deep sea holds a fascination for many of us but remains a frontier for discovery, with new species identified during almost every deep-sea expedition. This editorial provides an overview of deep-sea biological exploration, using technological advancement as a framework for summarizing deep-sea discoveries to show their development over time. We also describe some of the many challenges still associated with undertaking research in this remote environment. More qualified people, continued technological advancement and coordinated collaboration are crucial in these frontier regions, where species inventories and ecological understanding are limited. This editorial is the prelude to a selection of 15 recent papers on deep-sea biological discoveries published in the Zoological Journal of the Linnean Society.
Healthcare disparities in telemedicine for rheumatology care
Authors: Jackson Lesley E. , Danila Maria I.
Published: February 2022

Purpose of review

We summarize the recent literature published in the last 2 years on healthcare disparities observed in the delivery of rheumatology care by telemedicine. We highlight recent research dissecting the underpinnings of healthcare disparities and identify potentially modifiable contributing factors.

Recent findings

The COVID-19 pandemic has had major impacts on care delivery and has led to a pronounced increase in telemedicine use in rheumatology practice. Telemedicine services are disproportionately underutilized by racial/ethnic minority groups and among patients with lower socioeconomic status. Disparities in telemedicine access and use among vulnerable populations threatens to exacerbate existing outcome inequalities affecting people with rheumatic disease.

Telemedicine has the potential to expand rheumatology services by reaching traditionally underserved communities. However, some areas lack the infrastructure and technology to engage in telemedicine. Addressing health equity and the digital divide may help foster more inclusive telemedicine care.
Guided growth for coronal lower limb deformities in skeletal dysplasia
Authors: Kitoh Hiroshi , Kamiya Yasunari , Mishima Kenichi , Matsushita Masaki , Kaneko Hiroshi , Kitamura Akiko , Sawamura Kenta , Matsuyama Saori
Published: February 2022

Coronal angular deformities of the lower limbs are common in young children with skeletal dysplasia . The guided growth technique has been applied to correct deformities in children, but there are few comprehensive reports on the effectiveness of the procedure in skeletal dysplasia. We reviewed 44 limbs of 22 patients with various types of skeletal dysplasias who underwent guided growth surgery. Fifteen varus and 29 valgus limbs were treated with 102 epiphysiodesis. The average age at surgery, at implant removal, and at the latest examination was 10.4 ± 3.6 years, 11.8 ± 3.7 years and 14.1 ± 4.4 years, respectively. The mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (mMPTA), lateral distal tibial angle (mLDTA) and mechanical axis deviation (MAD) were measured from standing anteroposterior radiographs of both lower limbs. The mLDTA, mMPTA and MAD were successfully improved after surgery. Moderate or severe deformities were observed in 100% of the varus and 83% of the valgus limbs preoperatively, whereas only 14% of the varus and 20% of the valgus limbs had residual deformities at the latest examination. Correction of deformities was limited in some older children. Fifteen limbs (34%) required repeated implantations due to recurrence or inverted deformity. The guided growth surgery is effective in correcting coronal angular deformities in children with skeletal dysplasia with a limited risk of complications. The timing of surgery and implant removal is critical in obtaining satisfactory correction and preventing recurrence or inverted deformities.
Yes-associated protein 1 exerts its tumor-promoting effects and increases cisplatin resistance in tongue squamous cell carcinoma cells by dysregulating Hippo signal pathway
Authors: Guan Hua , Deng Linlin
Published: February 2022

Tongue squamous cell carcinoma (TSCC) has been well-known for its high metastasis and poor prognosis, but the molecular mechanisms of TSCC pathogenesis and chemoresistance are still largely unknown. Thus, the present study aimed to identify the involvement of a classic Hippo/Yes-associated protein 1 (YAP1) pathway in regulating TSCC progression and cisplatin (DDP) resistance. DDP-resistant TSCC cell lines were established by gradual exposure to DDP. Through western blot analysis, the protein expression of Hippo/YAP1 axis in TSCC tissues and cell lines was detected separately. Then, YAP1 was inhibited or overexpressed in TSCC cells. Cell viability and drug resistance were evaluated by cell counting kit-8 method, colony formation assay and Trypan blue staining assay. Cell migration ability was measured by Transwell assay. The Hippo pathway was dysregulated, and YAP1 was upregulated and dephosphorylated in the TSCC tissues or DDP-resistant cell lines, compared with normal tissues or DDP-sensitive cells. YAP1 knockdown inhibited cell proliferation, colony formation ability and migration, whereas overexpression of YAP1 exacerbated these malignant characteristics. YAP1 knockdown increased DDP-sensitivity by reducing the RAD51-mediated DNA damage repair behavior under DDP intervention in the DDP-resistant TSCC cells. Conversely, YAP1 overexpression significantly increased DDP-resistance by enhancing the RAD51-mediated DNA damage repair behavior under DDP intervention in the DDP-sensitive TSCC cells. In a word, upregulation and dephosphorylation of YAP1 caused dysregulation of the tumor-inhibiting Hippo pathway, resulting in the aggressiveness and DDP resistance in TSCC.
Biodegradable controlled-release polymer containing butylidenephthalide to treat a recurrent cervical spine glioblastoma with promising result: a compassionate trial report
Authors: Pan Yan-Hong , Lin Shinn-Zong , Chiu Tsung-Lang
Published: February 2022

Intramedullary spinal glioblastoma multiforme (GBM) tends to recur within 11 months of surgical resection, even after adjuvant chemoradiation therapy. Treatment options for recurrent spinal GBM are often limited. (Z)-n-butylidenephthalide [(Z)-BP] is a natural compound that induces apoptosis, antiproliferation, anti-invasion and antistemness effects in GBM cells. The Cerebraca wafer consists of (Z)-BP within a biodegradable wafer that can be implanted in the parenchyma of the central nervous system to treat high-grade glioma. We present a 44-year-old woman with a recurrent spinal GBM who underwent microscopic surgical tumor excision under fluorescein sodium guidance and intraoperative neurophysiologic monitoring. Four Cerebraca wafers were implanted into the cord and intradural space during the operation. MRI revealed that both tumor volume and spinal cord edema had decreased 4 days after surgery; both had substantially decreased 16 months after surgery. Neurologic functions and quality of life were improved after salvage therapy. No adverse events were reported. Cerebraca wafer implantation during surgical re-excision of spinal GBM may be a novel therapeutic approach for reduction of the tumor size and subsequent spinal cord edema with no toxicity to the spinal cord.
circBIRC6 contributes to the development of non-small cell lung cancer via regulating microRNA-217/amyloid beta precursor protein binding protein 2 axis
Authors: Ni Da , Teng Jiping , Cheng Youshuang , Zhu Zhijun , Zhuang Bufeng , Yang Zhiyin
Published: February 2022

Background:

Circular RNAs (circRNAs) are considered to be important regulators in cancer biology. In this study, we focused on the effect of circRNA baculoviral inhibitor of apoptosis protein (IAP) repeat containing 6 (circBIRC6) on non-small cell lung cancer (NSCLC) progression.

Methods:

The NSCLC and adjacent non-tumor tissues were collected at Shanghai Ninth People's Hospital. Quantitative real-time polymerase chain reaction was conducted for assessing the levels of circBIRC6, amyloid beta precursor protein binding protein 2 (APPBP2) messenger RNA (mRNA), baculoviral IAP repeat containing 6 mRNA (BIRC6), and microRNA-217 (miR-217). Western blot assay was adopted for measuring the protein levels of APPBP2, E-cadherin, N-cadherin, and vimentin. Colony formation assay, transwell assay, and flow cytometry analysis were utilized for evaluating cell colony formation, metastasis, and apoptosis. Dualluciferase reporter assay and RNA immunoprecipitation assay were carried out to determine the interaction between miR-217 and circBIRC6 and APPBP2 in NSCLC tissues. The murine xenograft model assay was used to investigate the function of circBIRC6 in tumor formation in vivo. Differences were analyzed via Student's t test or one-way analysis of variance. Pearson's correlation coefficient analysis was used to analyze linear correlation.

Results:

CircBIRC6 was overexpressed in NSCLC tissues and cells. Knockdown of circBIRC6 repressed the colony formation and metastasis and facilitated apoptosis of NSCLC cells in vitro and restrained tumorigenesis in vivo. Mechanically, circBIRC6 functioned as miR-217 sponge to promote APPBP2 expression in NSCLC cells. MiR-217 inhibition rescued circBIRC6 knockdown-mediated effects on NSCLC cell colony formation, metastasis, and apoptosis. Overexpression of miR-217 inhibited the malignant phenotypes of NSCLC cells, while the effects were abrogated by elevating APPBP2.

Conclusion:

CircBIRC6 aggravated NSCLC cell progression by elevating APPBP2 via sponging miR-217, which might provide a fresh perspective on NSCLC therapy.
Clusterin as a serum biomarker candidate contributes to the lung fibroblasts activation in chronic obstructive pulmonary disease
Authors: Zhang Qiang , Yue Yuanyi , Zheng Rui
Published: February 2022

Background:

Fibrosis in the peripheral airways contributes to airflow limitation in patients with chronic obstructive pulmonary disease (COPD). However, the key proteins involved in its development are still poorly understood. Thus, we aimed to identify the differentially expressed proteins (DEPs) between smoker patients with and without COPD and elucidate the molecular mechanisms involved by investigating the effects of the identified biomarker candidate on lung fibroblasts.

Methods:

The potential DEPs were identified by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis. The messenger RNA and protein levels of clusterin (CLU) in COPD patients and 12% cigarette smoke extract (CSE)-treated human bronchial epithelial cells were determined at the indicated time points. Furthermore, an in vitro COPD model was established via the administration of 8% CSE to normal human lung fibroblasts (NHLFs) at indicated time points. The effects of CSE treatment and CLU silencing on proliferation and activation of lung fibroblasts were analyzed.

Results:

A total of 144 DEPs were identified between COPD patients and normal smokers. The iTRAQ-based proteomics and bioinformatics analyses identified CLU as a serum biomarker candidate. We also discovered that CLU levels were significantly increased (P 
< 0.0001) in Global Initiative for Obstructive Lung Disease II, III, and IV patients and correlated (P 
< 0.0001) with forced expiratory volume in 1 s (R = −0.7705), residual volume (RV) (R = 0.6281), RV/total lung capacity (R = 0.5454), and computerized tomography emphysema (R = 0.7878). Similarly, CLU levels were significantly increased in CSE-treated cells at indicated time points (P < 0.0001). The CSE treatment significantly inhibited the proliferation, promoted the inflammatory response, differentiation of NHLFs, and collagen matrix deposition, and induced the apoptosis of NHLFs; however, these effects were partially reversed by CLU silencing.

Conclusion:

Our findings suggest that CLU may play significant roles during airway fibrosis in COPD by regulating lung fibroblast activation.
Phase II study of apatinib combined with temozolomide in patients with advanced melanoma after failure of immunotherapy
Authors: Zhou Li , Yang Yue , Si Lu , Chi Zhihong , Sheng Xinan , Lian Bin , Wang Xuan , Tang Bixia , Mao Lili , Yan Xieqiao , Li Siming , Bai Xue , Guo Jun , Cui Chuanliang
Published: February 2022

Treatment for advanced melanoma after progression on immunotherapy is limited. This phase II trial (NCT03422445) was conducted to evaluate the efficacy and safety of apatinib plus temozolomide in patients with advanced melanoma after failure of immunotherapy. Patients with unresectable stage III or stage IV melanoma after progression on immunotherapy were treated with temozolomide 300 mg on days 1–5 and apatinib 500 mg daily every 28-day cycle until disease progression or intolerable toxicities. Besides immunotherapy, prior chemotherapy, targeted therapy, and clinical trials were allowed. The primary endpoint was progression-free survival. Secondary endpoints were objective response rate, disease control rate, overall survival, and safety. Of 29 patients, 28 (96.6%) had metastatic diseases, and the predominant subtypes were mucosal [12 (41.4%)] and acral melanoma [eight (27.6%)]. Five (17.2%) patients showed BRAF, CKIT, or NRAS mutation. Five achieved confirmed partial response, with an objective response rate of 17.2%. The disease control rate was 82.8%. The median progression-free survival was 5.0 months [95% confidence interval (CI): 4.7–5.3], and the median overall survival was 10.1 months (95% CI: 5.1–15.0). Grade 3–4 treatment-related adverse events included proteinuria [four (13.8%)], thrombocytopenia [two (6.9%)], hypertension [one (3.4%)], and hyperbilirubinemia [one (3.4%)]. No treatment-related death occurred. Apatinib plus temozolomide demonstrated promising efficacy and manageable safety profile in patients with advanced melanoma after progression on immunotherapy.
Effect on surgery outcomes owing to the interval between onset of symptoms and surgery of patients with acute type A aortic dissection
Authors: Li Shouming , Wei Duoliang , Wang Zhenhua , Song Han , Cheng Shaopeng , Zhao Xin
Published: February 2022

Background:

This study aimed to identify whether the interval from onset of symptoms to surgery affects the outcomes of surgery in patients with acute type A aortic dissection (AAAD).

Methods:

This study retrospectively examined 249 patients with AAAD who underwent Sun's procedure. All patients were divided into 2 groups, hyperacute and acute, according to the interval from onset of symptoms to surgery. The primary endpoint was all-cause early mortality, and the secondary endpoint was early reoperation.

Results:

The surgery time, cardiopulmonary bypass time, clamp time, and selective cerebral perfusion time were not significantly different between the 2 groups. The intensive care unit length of stay and duration of mechanical ventilation of the 2 groups were 185.50 hours versus 185.00 hours (P = 0.970) and 41.50 hours versus 44.00 hours (P = 0.678), respectively. There were 52 early deaths: 29 in the hyperacute group and 23 in the acute group (21.6% vs. 20.0%, P = 0.751). The incidence of reoperation was 0.7% and 0.9% (P > 0.999), respectively. The incidence rates of postoperative acute heart failure (AHF), acute respiratory failure (ARF), nervous dysfunction, and acute kidney injury were 37.3% versus 25.2% (P = 0.041), 51.5% versus 51.3% (P = 0.976), 13.4% versus 7.0% (P = 0.096), and 37.3% versus 37.4% (P = 0.990), respectively. Multivariable analysis indicated that surgery in the hyperacute phase might be an independent risk factor for AHF (OR: 1.765; 95% CI: 1.021–3.052; P = 0.042).

Conclusion:

Surgery in the hyperacute phase of AAAD was associated with postoperative AHF. Therefore, early medical management or interventional therapy for complications before surgery performed by experienced surgeons is recommended, especially in the hyperacute phase.
24-hour Perfusion of Porcine Myocutaneous Flaps Mitigates Reperfusion Injury: A 7-day Follow-up Study
Authors: Brouwers Kaj , Thijssen Max F. , Kruit Anne Sophie , van Midden Dominique , Koers Erik J. , Zegers Her J.H. , Hummelink Stefan , Ulrich Dietmar J.O.
Published: February 2022

Background:

Static cold storage is the gold standard of preservation in vascularized composite allotransplantation and allows a preservation time of 4–6 hours. Machine preservation is a promising technique for prolonged preservation; however, studies on extended preservation that compare different preservatives are scarce. This study aims to assess the feasibility of 24-hour acellular perfusion and compares different preservation solutions in a porcine myocutaneous flap replantation model.

Methods:

Six harvested bilateral myocutaneous flaps of three Dutch Landrace pigs were perfused hypothermically for 24 hours with University of Wisconsin machine perfusion solution (UW-MPS; n = 2) or histidine-tryptophan-ketoglutarate solution (HTK; n = 2) or preserved on ice for 4 hours (n = 2) before orthotopic replantation. Animals were observed for 7 days after replantation. Skeletal muscle injury was assessed by biochemical markers during perfusion, and muscle biopsies were analyzed for ischemia reperfusion injury directly after preservation and at 1, 3, and 7 days after replantation.

Results:

Markers of muscle damage varied during perfusion, but decreased overall in both perfusion groups. Flap weight increased 60% and 97% in the HTK-perfused flaps, compared with -6% and -7% in the UW-MPS-perfused flaps after 24 hours. Histopathologic evaluation demonstrated decreased muscle damage in flaps perfused with HTK compared with the UW-MPS-perfused flaps at 1 week after replantation.

Conclusions:

Machine perfusion of myocutaneous flaps for 24 hours with subsequent replantation is feasible, but warrants further research. Perfusion with HTK solution seemed to result in better histological outcomes 7 days after reperfusion compared with UW-MPS.
Polymeric Drug Delivery Devices: Role in Cornea and External Disease
Authors: Roy Aravind , Krishna Venuganti Venkata V. , Chauhan Shreya S. , Garg Prashant
Published: February 2022

The field of ophthalmic drug delivery is undergoing rapid changes not only in the evolution of pharmacologic agents but also in the novel drug delivery vehicles. The ocular surface has limitations to drug penetration because of the presence of tight junctions between basal epithelial cells, which limits the amount of drug that can be absorbed after topical instillation. In addition, nasolacrimal drainage reduces the precorneal residence time significantly. Contact lenses (CLs) have been considered as possible carriers for topical medications because they reside on the ocular surface for a sufficient length of time, and pharmacologic agents may be copolymerized with hydrogels allowing controlled drug diffusion. This strategy reduces the frequency of dosage while improving compliance. Modification of drug delivery vehicles is essential to allow sustained release of the drug from a polymeric complex, facilitate stability and residence time of the drug on the precorneal tear film, and improve penetration into biologic membranes. This review focuses on updates in CL-based and non-CL–based strategies in ophthalmic drug delivery.
Management of Keratoconus With Corneal Rigid Gas-Permeable Contact Lenses
Authors: Itoi Motozumi , Itoi Motohiro
Published: February 2022

Vision correction using a corneal rigid gas-permeable contact lens, which is relatively safe, easy to replace, and economical, is still the basis of the management for keratoconus. For eyes with keratoconus, two fitting strategies have traditionally been used in Japan: apical touch fitting with spherical lenses and parallel fitting with multicurve lenses. These two techniques have different success rates depending on the type and severity of keratoconus. Therefore, it is important to classify eyes with keratoconus into four types according to the shape of the cornea and select the prescription techniques according to this classification. If the corneal GPs prescribed by these fitting methods cannot be used because of mechanical irritation to the corneal epithelium, the “piggyback lens system” is an effective option. Furthermore, proper lens care must be instructed to patients to prevent contact lens-related complications and maintain visual function. If these fittings and introductions can be performed properly, corneal GPs can safely provide effective and comfortable vision for many patients with keratoconus, even for those with severe keratoconus.