Pancreatic cancer stem cells:Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a fve-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells （PCSCs） contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are revi-ewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic tar-gets are also discussed with a focus on selected speci-fic inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specifc drug delivery are highlighted, and their limitations considered.

Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions

Neurodegeneration is one of the biggest public health problems in modern society. Age-associated neurodegeneration, which is accelerated several-fold in Alzheimer＇s disease （AD） alone, is not only an enormous social and economic burden to the affected in- dividuals and their families, but is also a great scientific challenge. Currently 25-35 million people worldwide suffer from AD, the single largest cause of dementia in middle- to old-aged individuals. These numbers are projected to triple by 2050 if no treatment to prevent or reverse AD is developed.

MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches

A review of recent animal models of amyotrophic lateral sclerosis showed a large number of mi RNAs had altered levels of expression in the brain and spinal cord,motor neurons of spinal cord and brainstem,and hypoglossal,facial,and red motor nuclei and were mostly upregulated.Among the mi RNAs found to be upregulated in two of the studies were mi R-21,mi R-155,mi R-125 b,mi R-146 a,mi R-124,mi R-9,and mi R-19 b,while those downregulated in two of the studies included mi R-146 a,mi R-29,mi R-9,and mi R-125 b.A change of direction in mi RNA expression occurred in some tissues when compared(e.g.,mi R-29 b-3 p in cerebellum and spinal cord of wobbler mice at 40 days),or at different disease stages(e.g.,mi R-200 a in spinal cord of SOD1(G93 A)mice at 95 days vs.108 and 112 days).In the animal models,suppression of mi R-129-5 p resulted in increased lifespan,improved muscle strength,reduced neuromuscular junction degeneration,and tended to improve motor neuron survival in the SOD1(G93 A)mouse model.Suppression of mi R-155 was also associated with increased lifespan,while lowering of mi R-29 a tended to improve lifespan in males and increase muscle strength in SOD1(G93 A)mice.Overexpression of members of mi R-17~92 cluster improved motor neuron survival in SOD1(G93 A)mice.Treatment with an artificial mi RNA designed to target h SOD1 increased lifespan and improved muscle strength in SOD1(G93 A)animals.Further studies with animal models of amyotrophic lateral sclerosis are warranted to validate these findings and identify specific mi RNAs whose suppression or directed against h SOD1 results in increased lifespan,improved muscle strength,reduced neuromuscular junction degeneration,and improved motor neuron survival in SOD1(G93 A)animals.

Promising therapeutic approaches using CRISPR/Cas9 genome editing technology in the treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy is an X-linked recessive hereditary monogenic disorder caused by inability to produce dystrophin protein.In most patients,the expression of dystrophin lost due to disrupting mutations in open reading frame.Despite the efforts in a large number of different therapeutic approaches to date,the treatments available for DMD remain mitigative and supportive to improve the symptoms of the disease,rather than to be curative.The advent of CRISPR/Cas9 technology has revolutionized genome editing scope and considered as pioneer in effective genomic engineering.Deletions or excisions of intragenic DNA by CRISPR as well as a similar strategy with exon skipping at the DNA level induced by antisense oligonucleotides,are new and promising approaches in correcting DMD gene,which restore the expression of a truncated but functional dystrophin protein.Also,CRISPR/Cas9 technology can be used to treat DMD by removing duplicated exons,precise correction of causative mutation by HDR-based pathway and inducing the expression of compensatory proteins such as utrophin.In this study,we briefly explained the molecular genetics of DMD and a historical overview of DMD gene therapy.We in particular focused on CRISPR/Cas9-mediated therapeutic approaches that used to treat DMD.

Advanced glycation end products in gastric cancer:A promising future

In this editorial,we delve into the article and offer valuable insights into a crucial aspect of gastric cancer aetiology.Gastric cancer is a malignancy emanating from the epithelial lining of the gastric mucosa and one of the most prevalent forms of cancer worldwide.The development of gastric cancer is associated with multiple risk factors,including Helicobacter pylori infection,advanced age,a diet rich in salt,and suboptimal eating patterns.Despite notable reductions in morbidity and mortality rates,gastric cancer remains a formidable public health concern,impacting patients’lives.Advanced glycation end products(AGEs)are complex compounds arising from nonenzymatic reactions within living organisms,the accumulation of which is implicated in cellular and tissue damage;thus,the levels are AGEs are correlated with the risk of diverse diseases.The investigation of AGEs is of paramount importance for the treatment of gastric cancer and can provide pivotal insights into disease pathogenesis and preventive and therapeutic strategies.The reduction of AGEs levels and suppression of their accumulation are promising avenues for mitigating the risk of gastric cancer.This approach underscores the need for further research aimed at identifying innovative interventions that can effectively lower the incidence and mortality rates of this malignancy.

Adipose-derived stem cells:Pathophysiologic implications vs therapeutic potential in systemic sclerosis

Adipose-derived stem cells(ADSCs)residing in the stromal vascular fraction(SVF)of white adipose tissue are recently emerging as an alternative tool for stem cell-based therapy in systemic sclerosis(SSc),a complex connective tissue disorder affecting the skin and internal organs with fibrotic and vascular lesions.Several preclinical and clinical studies have reported promising therapeutic effects of fat grafting and autologous SVF/ADSC-based local treatment for facial and hand cutaneous manifestations of SSc patients.However,currently available data indicate that ADSCs may represent a double-edged sword in SSc,as they may exhibit a pro-fibrotic and anti-adipogenic phenotype,possibly behaving as an additional pathogenic source of pro-fibrotic myofibroblasts through the adipocyte-to-myofibroblast transition process.Thus,in the perspective of a larger employ of SSc-ADSCs for further therapeutic applications,it is important to definitely unravel whether these cells present a comparable phenotype and similar immunosuppressive,anti-inflammatory,anti-fibrotic and pro-angiogenic properties in respect to healthy ADSCs.In light of the dual role that ADSCs seem to play in SSc,this review will provide a summary of the most recent insights into the preclinical and clinical studies employing SVF and ADSCs for the treatment of the disease and,at the same time,will focus on the main findings highlighting the possible involvement of these stem cells in SSc-related fibrosis pathogenesis.

Crimean-Congo hemorrhagic fever from the immunopathogenesis, clinical, diagnostic, and therapeutic perspective: A scoping review

Crimean-Congo hemorrhagic fever virus(CCHFV) is responsible for widespread tick-borne zoonotic viral disease CCHF in African, Middle Eastern, Asian, and European countries. CCHFV can be spread to humans through tick bites or contact with infected animals or humans, and it often progresses from asymptomatic to severe/lethal illness, with fatality rates ranging from 10% to 40% in humans. Today, CCHF is growing into a significant public health concern due to its very high prevalence, severity of the condition, and lack of available vaccines and specific treatments. Recent research has been drawn towards a more accurate study of CCHFV characteristics, including the structure, genetic diversity, mechanisms involved in pathogenesis and immunopathogenesis, and clinical features. In addition, the use of animal models(mouse and non-human primates) and advanced diagnostic tools in recent years has resulted in a significant advance in CCHF related studies. In this context, we summarized the latest findings about CCHF research, its health complications, animal models, current diagnosis, vaccination, and CCHF treatments, and therapeutic strategies. Furthermore, we discussed existing deficiencies and problems in CCHFV analysis, as well as areas that still need to yield conclusive answers.

Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease

AIM To determine the clinical effectiveness of nutritional counseling on reduction of non-alcoholic fatty liver disease(NAFLD) severity, weight loss, metabolic and anthropometric indexes and liver enzymes.METHODS Forty-six adults with NAFLD received a 6-mo clinical and a dietary intervention(based on Mediterranean diet) carried out respectively by a gastroenterologist and a nutritionist with counseling license. The counseling process consisted of monthly meeting(about 45 min each). The effect of the treatment was evaluated monitoring liver enzymes, metabolic parameters, cardiovascular risk indexes, NAFLD severity [assessed by ultrasound(US)] and related indexes. All parameters were assessed at baseline. Biochemistry was also assessed at mid-and end-interventions and US was repeated at end-intervention.RESULTS The percentage of patients with steatosis grade equal or higher than 2 was reduced from 93% to 48% and steatosis regressed in 9 patients(20%). At the end of the treatment the end-point concerning the weight(i.e., a 7% weight reduction or achievement/maintenance of normal weight) was accomplished by 25 out of 46 patients(i.e., 54.3%). As far as the liver enzymes is concerned, all three liver enzymes significantly decrease during the treatment the normalization was particularly evident for the ALT enzyme(altered values reduced from 67% down to 11%). Several parameters, i.e., BMI, waist circumference, waist-to-hip ratio, AST, ALT, GGT, HDL, serum glucose, Tot-Chol/HDL, LDL/HDL, TG/HDL, AIP, HOMA, FLI, Kotronen index, VAI, NAFLD liver fat score and LAP, showed a significant improvement(P < 0.01) between baseline and end-treatment.CONCLUSION Outcomes of this study further strengthen the hypothesis that Med Diet and more active lifestyle can be considered a safe therapeutic approach for reducing risk and severity of NAFLD and related disease states. The proposed approach may be proposed as a valid and recommended approach for improving the clinical profile of NAFLD patients.

Pancreatic metastases from renal cell carcinoma:The state of the art

Pancreatic metastases are rare,with a reported incidence varying from 1.6%to 11%in autopsy studies of patients with advanced malignancy.In clinical series,the frequency of pancreatic metastases ranges from 2%to 5%of all pancreatic malignant tumors.However,the pancreas is an elective site for metastases from carcinoma of the kidney and this peculiarity has been reported by several studies.The epidemiology,clinical presentation,and treatment of pancreatic metastases from renal cell carcinoma are known from singleinstitution case reports and literature reviews.Thereis currently very limited experience with the surgical resection of isolated pancreatic metastasis,and the role of surgery in the management of these patients has not been clearly defined.In fact,for many years pancreatic resections were associated with high rates of morbidity and mortality,and metastatic disease to the pancreas was considered to be a terminal-stage condition.More recently,a significant reduction in the operative risk following major pancreatic surgery has been demonstrated,thus extending the indication for these operations to patients with metastatic disease.

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis

The liver has a vital role in many metabolic and regulatory processes in the body.Primary biliary cholangitis(PBC),previously known as primary biliary cirrhosis,is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens.At this time there is no definitive cure for PBC;however,ursodeoxycholic acid(UDCA)has been shown to reduce injury when administered as the first line of treatment.Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression.Currently,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus.This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

Pharmacogenomics in oncology

Precision therapy in the field of oncology is rapidly developing. Numerous somatic genetic markers in eg tyrosine kinase receptors or transcription factors have been identified to be indicative for the treatment with anti-cancer drugs. In contrast, only some recommendations have been developed considering hereditary variants in drug metabolizing enzymes such as TPMT, DYPD or UGT1A1. Although a huge knowledge has been gained on the association of drug transporters variants such as ABCB1 or ABCG2 and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. However, there is increasing evidence that individual phenotypic differences may result not only from genetics, but also from epigenetic alterations such as histone-acetylation or DNA-methylation. Moreover,interactions with non-coding RNAs contribute to protein expression and may modulate drug action. Currently intriguing developments of novel therapeutic approaches through epigenetic drugs are emerging. The overall complexity of epigenetics in drug action is so far only little understood. Of significant importance are the consequences of mi RNA interaction for drug resistance in cancer by regulating target genes and efflux transporters. Further intriguing findings address DNAmethylation as modifier of transporter function and its consequences in cancer development and treatment. The progress of science may lead to the discovery of rare, but functionally relevant SNPs and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

Microsurgical resection of craniopharyngioma of the third ventricle via an improved transventricular approach

Background Craniopharyngioma of the third ventricle is difficult to treat and its therapeutic regimens and operative approaches have been controversial. This study was undertaken to probe indications for microsurgical resection of craniopharyngioma of the third ventricle via an improved transventricular approach, its surgical procedures and therapeutic effects, and prevention of postoperative complications.Methods Fifty-one patients with craniopharyngioma of the third ventricle were treated from January 2000 to October 2004 by an improved transventricular approach for removing the tumor via the interventricular foramen,the intermedius of the septum pellucidum or choroid fissure. Symptoms and signs of the patients, and results of imaging, operation, and follow-up were analyzed. Results Of the 51 patients who had received the improved transventricular resection, 4 underwent a combined approach with an entrance of the pterion. Forty patients (78.43%) underwent total resection and others subtotal resection, without an operative death. Epileptic seizures were found in 3 patients (5.88%) and subdural effusion in the operative field in 4 (7.84%). All patients showed good general conditions after operation, and follow-up for an average of 27.52 months showed relapse of the tumour in 8 patients (15.69%).Conclusions Microsurgical resection of craniopharyngioma of the third ventricle by an improved transventricular approach has advantages of operative safety and efficacy, lower mortality and disability, and less complications.

Regulating the microenvironment with nanomaterials:Potential strategies to ameliorate COVID-19

COVID-19,caused by SARS-CoV-2,has resulted in serious economic and health burdens.Current treatments remain inadequate to extinguish the epidemic,and efficient therapeutic approaches for COVID-19 are urgently being sought.Interestingly,accumulating evidence suggests that microenvironmental disorder plays an important role in the progression of COVID-19 in patients.In addition,recent advances in nanomaterial technologies provide promising opportunities for alleviating the altered homeostasis induced by a viral infection,providing new insight into COVID-19 treatment.Most literature reviews focus only on certain aspects of microenvironment alterations and fail to provide a comprehensive overview of the changes in homeostasis in COVID-19 patients.To fill this gap,this review systematically discusses alterations of homeostasis in COVID-19 patients and potential mechanisms.Next,advances in nanotechnology-based strategies for promoting homeostasis restoration are summarized.Finally,we discuss the challenges and prospects of using nanomaterials for COVID-19 management.This review provides a new strategy and insights into treating COVID-19 and other diseases associated with microenvironment disorders.

Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer’s disease

Alzheimer’s disease(AD)is an age-related neurodegenerative disorder,characterized clinically by insidious onset of memory and cognition impairment,emergence of psychiatric symptoms and behavioral disorder,and impairment of activities of daily living(ADL).Traditional Chinese medicine(TCM)is practiced in the Chinese health care system for more than 2,000 years.In recent years,scientists have isolated many novel compounds from herbs,some of which improve dementia with fewer side effects than conventional drugs and are regarded as potential anti-AD drugs.In this review,we summarize the latest research progress on TCM showing their possible role of treatment of AD and other demented diseases and possible pharmacological actions.