Drug resistance mechanisms in cancers:Execution of prosurvival strategies

One of the quintessential challenges in cancer treatment is drug resistance.Several mechanisms of drug resistance have been described to date,and new modes of drug resistance continue to be discovered.The phenomenon of cancer drug resistance is now widespread,with approximately 90% of cancer-related deaths associated with drug resistance.Despite significant advances in the drug discovery process,the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy.Therefore,understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities.In the present review,I discuss the different mechanisms of drug resistance in cancer cells,including DNA damage repair,epithelial to mesenchymal transition,inhibition of cell death,alteration of drug targets,inactivation of drugs,deregulation of cellular energetics,immune evasion,tumor-promoting inflammation,genome instability,and other contributing epigenetic factors.Furthermore,I highlight available treatment options and conclude with future directions.

A review of complications after ureteral reconstruction

Objective:This study aimed to provide a comprehensive overview of the complications unique to ureteral reconstruction in adults,emphasizing their presentation,diagnosis,and management in the treatment of ureteral structure disease.Methods:This review involves an in-depth analysis of existing literature and case studies pertaining to ureteral reconstruction,with a focus on examining the range of complications that can arise post-surgery.Special attention is given to the presentation of each complication,the diagnostic process involved,and the subsequent management strategies.Results:Ureteral reconstruction can treat ureteral stricture disease with low morbidity;however,complications,although uncommon,can have severe consequences.The most notable complications include urinary extravasation,stricture recurrence,urinary tract infections,compartment syndrome,symptomatic vesicoureteral reflux,and Boari flap necrosis.Each complication presents unique diagnostic challenges and requires specific management approaches.Conclusion:Ureteral reconstruction is a highly effective treatment for ureteral stricture disease.Having a strong understanding of the potential complications that patients may experience following ureteral reconstruction is not only critical to adequately counsel patients but also facilitate prompt diagnosis and management of complications when they arise.

Improving autoencoder-based unsupervised damage detection in uncontrolled structural health monitoring under noisy conditions

Structural health monitoring is widely utilized in outdoor environments,especially under harsh conditions,which can introduce noise into the monitoring system.Therefore,designing an effective denoising strategy to enhance the performance of guided wave damage detection in noisy environments is crucial.This paper introduces a local temporal principal component analysis(PCA)reconstruction approach for denoising guided waves prior to implementing unsupervised damage detection,achieved through novel autoencoder-based reconstruction.Experimental results demonstrate that the proposed denoising method significantly enhances damage detection performance when guided waves are contaminated by noise,with SNR values ranging from 10 to-5 dB.Following the implementation of the proposed denoising approach,the AUC score can elevate from 0.65 to 0.96 when dealing with guided waves corrputed by noise at a level of-5 dB.Additionally,the paper provides guidance on selecting the appropriate number of components used in the denoising PCA reconstruction,aiding in the optimization of the damage detection in noisy conditions.

Lin28 as a therapeutic target for central nervous system regeneration and repair

Axon disconnection in the central nervous system(CNS) usually causes signal transduction failure and severe functional deficits in patients with neurological disorders. Currently, there is no cure for patients with CNS axon injury and they usually suffer from life-long neurological defects(e.g., paralysis, loss of sensory function, and autonomic dysfunction) and life-threatening complications(e.g., autonomic dysreflexia).

Actin(g) toward a revised understanding of the role of cytoskeletal dynamics in neuronal bioenergetics

Neurons are energy-demanding cells.Disruptions in energy metabolism can quickly interrupt neuronal function,leading to cell death and neurodegeneration.For instance,ischemia rapidly depletes adenosine triphosphate(ATP)thereby disrupting energy-dependent cellular processes crucial for homeostasis,and axon degeneration is preceded by a collapse of axonal ATP levels.

Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Analysis on unit maximum capacity of orthogonal multiple watermarking for multimedia signals in B5G wireless communications

Beyond-5G(B5G)aims to meet the growing demands of mobile traffic and expand the communication space.Considering that intelligent applications to B5G wireless communications will involve security issues regarding user data and operational data,this paper analyzes the maximum capacity of the multi-watermarking method for multimedia signal hiding as a means of alleviating the information security problem of B5G.The multiwatermarking process employs spread transform dither modulation.During the watermarking procedure,Gram-Schmidt orthogonalization is used to obtain the multiple spreading vectors.Consequently,multiple watermarks can be simultaneously embedded into the same position of a multimedia signal.Moreover,the multiple watermarks can be extracted without affecting one another during the extraction process.We analyze the effect of the size of the spreading vector on the unit maximum capacity,and consequently derive the theoretical relationship between the size of the spreading vector and the unit maximum capacity.A number of experiments are conducted to determine the optimal parameter values for maximum robustness on the premise of high capacity and good imperceptibility.

Prediction of Damping Capacity Demand in Seismic Base Isolators via Machine Learning

Base isolators used in buildings provide both a good acceleration reduction and structural vibration control structures.The base isolators may lose their damping capacity over time due to environmental or dynamic effects.This deterioration of them requires the determination of the maintenance and repair needs and is important for the long-termisolator life.In this study,an artificial intelligence prediction model has been developed to determine the damage and maintenance-repair requirements of isolators as a result of environmental effects and dynamic factors over time.With the developed model,the required damping capacity of the isolator structure was estimated and compared with the previously placed isolator capacity,and the decrease in the damping property was tried to be determined.For this purpose,a data set was created by collecting the behavior of structures with single degrees of freedom(SDOF),different stiffness,damping ratio and natural period isolated from the foundation under far fault earthquakes.The data is divided into 5 different damping classes varying between 10%and 50%.Machine learning model was trained in damping classes with the data on the structure’s response to random seismic vibrations.As a result of the isolator behavior under randomly selected earthquakes,the recorded motion and structural acceleration of the structure against any seismic vibration were examined,and the decrease in the damping capacity was estimated on a class basis.The performance loss of the isolators,which are separated according to their damping properties,has been tried to be determined,and the reductions in the amounts to be taken into account have been determined by class.In the developed prediction model,using various supervised machine learning classification algorithms,the classification algorithm providing the highest precision for the model has been decided.When the results are examined,it has been determined that the damping of the isolator structure with the machine learning method is predicted successfully at a level exceeding 96%,and it is an effective method in deciding whether there is a decrease in the damping capacity.

Optical redox imaging of ANT1-de-cient muscles

Adenine nucleotide translocator(ANT)is a mitochondrial protein involved in the exchange of ADP and ATP across the mitochondrial inner membrane.It plays a crucial role in cellular energy metabolism by facilitating the transport of ATP synthesized within the mitochondria to the cytoplasm.The isoform ANT1 predominately expresses in cardiac and skeletal muscles.Mutations or dysregulation in ANT1 have been implicated in various mitochondrial disorders and neuromuscular diseases.We aimed to examine whether ANT1 deletion may affect mitochondrial redox state in our established ANT1-de-cient mice.Hearts and quadriceps resected from age-matched wild type(WT)and ANT1-de-cient mice were snap-frozen in liquid nitrogen.The Chance redox scanner was utilized to perform 3D optical redox imaging.Each sample underwent scanning across 3–5 sections.Global averaging analysis showed no signi-cant differences in the redox indices(NADH,flavin adenine dinucleotide containing-flavoproteins Fp,and the redox ratio Fp/(NADH+Fp)between WT and ANT1-de-cient groups.However,quadriceps had higher Fp than hearts in both groups(p¼0:0004 and 0.01,respectively).Furthermore,the quadriceps were also more oxidized(a higher redox ratio)than hearts in WT group(p¼0:004).NADH levels were similar in all cases.Our data suggest that under non-stressful physical condition,the ANT1-de-cient muscle cells were in the same mitochondrial state as WT ones and that the signi-cant difference in the mitochondrial redox state between quadriceps and hearts found in WT might be diminished in ANT1-de-cient ones.Redox imaging of muscles under physical stress can be conducted in future.

Challenges with non-descriptive compliance labeling of end-stage renal disease patients in accessibility for renal transplantation

Non-descriptive and convenient labels are uninformative and unfairly project blame onto patients.The language clinicians use in the Electronic Medical Record,research,and clinical settings shapes biases and subsequent behaviors of all providers involved in the enterprise of transplantation.Terminology such as noncompliant and nonadherent serve as a reason for waitlist inactivation and limit access to life-saving transplantation.These labels fail to capture all the circum-stances surrounding a patient’s inability to follow their care regimen,trivialize social determinants of health variables,and bring unsubstantiated subjectivity into decisions regarding organ allocation.Furthermore,insufficient Medicare coverage has forced patients to ration or stop taking medication,leading to allograft failure and their subsequent diagnosis of noncompliant.We argue that perpetuating non-descriptive language adds little substantive information,in-creases subjectivity to the organ allocation process,and plays a major role in reduced access to transplantation.For patients with existing barriers to care,such as racial/ethnic minorities,these effects may be even more drastic.Transplant committees must ensure thorough documentation to correctly encapsulate the entirety of a patient’s position and give voice to an already vulnerable population.

The Sigma-1 Receptor as a Pharmacologic Chaperone: Energetics

Initially thought to be an opioid receptor subtype, Sigma-1 receptors (S1R) are now known to be unique proteins that have chaperone-like properties. As such, they play critical roles in cellular signaling, homeostasis, and cell survival. These roles offer significant insight for understanding homeostasis of normal physiologic processes, and the pathophysiologic consequences of disruption of normal function. Because of the broad nature of chaperone action, S1R agonists and antagonists represent potential drug discovery goals for the pharmacotherapeutic treatment of a variety of disorders that result from dysfunctional proteins. The present study summarizes the S1R as a pharmacologic chaperone crucial for protein folding and cellular homeostasis. Through literature review and thermodynamic analysis, it explores how S1R stabilizes target proteins, influencing neuroprotection and potential drug therapies. The binding of chaperones to target proteins is thermodynamically favorable, offering insights into treating diseases linked to protein misfolding.

Psychiatric Sequelae of Chronic Pruritic Dermatoses

This comprehensive review investigates the significant psychological impact and profound psychological comorbidities found in individuals suffering from chronic pruritic dermatoses, including atopic dermatitis, chronic urticaria, and prurigo nodularis. Highlighting the complex, reciprocal relationship between pruritus and psychiatric conditions such as depression, anxiety, and sleep disturbances, this paper elucidates the comprehensive impact of dermatological disorders on the skin in addition to the far-reaching effects on an individual’s psychological well-being. By evaluating the efficacy of integrated psychodermatological interventions, including cognitive behavioral therapy, mindfulness practices, pharmacological treatments, and innovative telepsychiatry and digital health solutions, this review aims to lay the foundation for a more holistic approach to treatment of concurrent dermatological and psychiatric conditions. Future research endeavors should delve deeper into the mechanistic foundation of the pruritus-psychiatry interface, the refinement of tailored treatment strategies, and the evaluation of long-term patient outcomes. In doing so, this review seeks to contribute to the optimization of patient care and well-being, underscoring the pivotal role of addressing both dermatological and psychological needs in achieving comprehensive health outcomes.

The Impact of Psychosocial Influences on Chronic Wound Healing

This comprehensive review explores the intricate dynamics between psychosocial factors and chronic wound healing processes, specifically focusing on prevalent conditions such as pressure ulcers, diabetic foot ulcers, and venous leg ulcers. By examining the roles of psychiatric conditions, including depression, anxiety, and post-traumatic stress disorder (PTSD), this paper illuminates how these factors intricately influence wound healing dynamics, including mechanisms of pain perception and inflammatory responses. Furthermore, we evaluate the effectiveness of integrated biopsychosocial interventions, which encompass a holistic approach to wound care, thereby enhancing healing outcomes for dermatology patients. Future studies should focus on investigating the specific psychosocial determinants that significantly influence wound healing, exploring novel therapeutic strategies, and implementing personalized interventions to meet the unique needs of each patient. Such endeavors hold promise in advancing the fields of psychodermatology and wound management, fostering a deeper understanding and application of psychosocial considerations in dermatological care.

Cardiac amyloidosis: state-of-the-art review

Cardiac amyloidosis(CA)is caused by deposition of amyloid fibrils in the myocardium and has two main sub-types,transthyretin cardiac amyloidosis(ATTR)and immunoglobulin light chain cardiac amyloidosis(AL).ATTR is further dif-ferentiated into wild-type(wtATTR)and hereditary(hATTR),depending on the absence or presence of mutation in the trans-thyretin gene.The increased recognition of disease with the improvement in diagnostic armamentarium and serendipitous ad-vancements in the therapeutic landscape have changed the status of CA from being a rare and untreatable disease to being a not-so-rare and treatable disease.Both ATTR and AL have certain clinical aspects that can provide early clues for the disease.While electrocardiography followed by echocardiography and subsequently cardiac magnetic resonance can raise suspicion for CA,the definitive diagnosis of ATTR is non-invasively established by bone scintigraphy while that of AL always needs histological con-firmation.Severity of CA can be gauged by serum biomarker-based staging of both ATTR and AL.ATTR therapies work by silen-cing or stabilizing TTR or by degrading amyloid fibrils,while AL is managed with anti-plasma cell therapies and autologous stem cell transplant.

Role of exercise in the brain:focus on oligodendrocytes and remyelination

The phrase“Mens sana in corpore sano”taken from Juvenal's Satires(127 a.C.)represents one of the best-known and most used sentences of all time,whose meaning in the modern age refers to the importance of physical activity for mental health and wellbeing.Robust literature demonstrated the positive role of exercise in counteracting several diseases,such as diabetes,cardiovascular diseases,neurodegenerative diseases,cancers and age-related disorders including muscle atrophy,the reduction of aerobic capacity,bone and cartilage loss.

Cancer screening and management in the transgender population:Review of literature and special considerations for gender affirmation surgery

BACKGROUND Literature focused on cancer screening and management is lacking in the transgender population.AIM To action to increase contributions to the scientific literature that drives the creation of cancer screening and management protocols for transgender and gender nonconforming(TGNC)patients.METHODS We performed a systematic search of PubMed on January 5th,2022,with the following terms:“TGNC”,OR“transgender”,OR“gender non-conforming”,OR“gender nonbinary”AND“cancer screening”,AND“breast cancer”,AND“cervical cancer”,AND“uterine cancer”,AND“ovarian cancer”,AND“prostate cancer”,AND“testicular cancer”,AND“surveillance”,AND“follow-up”,AND“management”.70 unique publications were used.The findings are discussed under“Screening”and“Management”categories.RESULTS Screening:Current cancer screening recommendations default to cis-gender protocols.However,long-term genderaffirming hormone therapy and loss to follow-up from the gender-specific specialties contribute to a higher risk for cancer development and possible delayed detection.The only known screening guidelines made specifically for this population are from the American College of Radiology for breast cancer.Management:Prior to undergoing Gender Affirmation Surgery(GAS),discussion should address cancer screening and management in the organs remaining in situ.Cancer treatment in this population requires consideration for chemotherapy,radiation,surgery and/or reconstruction.Modification of hormone therapy is decided on a case-by-case basis.The use of prophylactic vs aesthetic techniques in surgery is still debated.CONCLUSION When assessing transgender individuals for GAS,a discussion on the future oncologic risk of the sex-specific organs remaining in situ is essential.Cancer management in this population requires a multidisciplinary approach while the care should be highly individualized with considerations to social,medical,surgical and gender affirming surgery related specifications.Special considerations have to be made during planning for GAS as surgery will alter the anatomy and may render the organ difficult to sample for screening purposes.A discussion with the patient regarding the oncologic risk of remaining organs is imperative prior to GAS.Other special considerations to screening such as the conscious or unconscious will to unassociated with their remaining organs is also a key point to address.We currently lack high quality studies pertinent to the cancer topic in the gender affirmation literature.Further research is required to ensure more comprehensive and individualized care for this population.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype

BACKGROUND Tacrolimus extended-release tablets have been Food and Drug Administrationapproved for use in the de novo kidney transplant population.Dosing requirements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression.Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus,but this has not been established for tacrolimus extended-release tablets in the de novo setting.AIM To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype.METHODS Single-arm,prospective,single-center,open-label,observational study(ClinicalTrials.gov:NCT037-13645).Life cycle pharma tacrolimus(LCPT)orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight.If weight is more than 120%of ideal body weight,an adjusted body weight was used.LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL.Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion.RESULTS Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(6 d vs 13.5 d vs 4.5 d;P=0.025).Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(16 mg vs 16 mg vs 12 mg;P=0.010)(0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg;P=0.018).CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers(7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL;P=00.008).No differences were identified with regards to kidney graft function at 30-d post-transplant.Serious adverse events were reported for 13(36%)patients.CONCLUSION Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacrolimus to achieve target trough concentrations.We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

PartLabeling:A label management framework in 3D space

Background In this work,we focus on the label layout problem:specifying the positions of overlaid virtual annotations in Virtual/Augmented Reality scenarios.Methods Designing a layout of labels that does not violate domain-specific design requirements,while at the same time satisfying aesthetic and functional principles of good design,can be a daunting task even for skilled visual designers.Presenting the annotations in 3D object space instead of projection space,allows for the preservation of spatial and depth cues.This results in stable layouts in dynamic environments,since the annotations are anchored in 3D space.Results In this paper we make two major contributions.First,we propose a technique for managing the layout and rendering of annotations in Virtual/Augmented Reality scenarios by manipulating the annotations directly in 3D space.For this,we make use of Artificial Potential Fields and use 3D geometric constraints to adapt them in 3D space.Second,we introduce PartLabeling:an open source platform in the form of a web application that acts as a much-needed generic framework allowing to easily add labeling algorithms and 3D models.This serves as a catalyst for researchers in this field to make their algorithms and implementations publicly available,as well as ensure research reproducibility.The PartLabeling framework relies on a dataset that we generate as a subset of the original PartNet dataset consisting of models suitable for the label management task.The dataset consists of 10003D models with part annotations.

Pilot Studies on the Novel Hypothesis that TSPO (Peripheral Benzodiazepine Receptor) Is Involved in Benzodiazepine/“Z-Drug” Physical Dependence and/or Withdrawal

Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.

室温下表面极化效应对量子点带隙和吸收峰波长的影响

对于离散在本底介质中的纳米晶体量子点,考虑表面极化效应,通过像电荷法建立极化势能项,应用微扰法求解激子的薛定谔方程,得到了与本底介电系数直接相关的量子点带隙解析表达式.对不同本底中尺寸依赖的量子点带隙、第一吸收峰波长、第一吸收峰波长移动进行的计算表明,表面极化效应对量子点的带隙和第一吸收峰波长有明显的影响.随着本底介电系数的增大,量子点的带隙减小,第一吸收峰波长红移.量子点在不同本底中的第一吸收峰波长移动会在某个固定粒径达到最大值,最大值对应的粒径取决于量子点种类.