Treatment Resistant Depression, Ketamine versus ECT

Recent studies have highlighted the increase in treatment resistant depression. Of particular concern is the rising trend of depression and suicide rates among Young Adults. Ketamine was approved for treatment resistant depression in 2019 by the US Food and Drug Administration. It received an additional indication for treatment of suicidality. While intranasal Ketamine is approved for depression, recent data about intravenous infusion of Ketamine in controlled inpatient settings has been promising. ECT has a long-standing trend for being used for resistant depression and recent comparison trials have revealed positive results when head-to-head comparisons are made with Ketamine. Future studies need to focus on patient selection and wherein treatment algorithm should Ketamine be selected as treatment modality.

Pharmacoepidemiologic study of association between apparent treatment resistant hypertension, cardiovascular disease and interaction effect by sex and age

BACKGROUND A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension(aTRH)and risk of cardiovascular disease(CVD).AIM To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association.METHODS We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT).ALLHAT recruited participants(n=25516)from 625 primary care settings throughout the United States,Canada,Puerto Rico,and United States Virgin Islands,aged 55 and older with hypertension and at least one additional risk factor for heart disease.aTRH was assessed from the year 2 visit.CVD event was defined as one of the following from the year 2 follow-up visit:Fatal or non-fatal myocardial infarction,coronary revascularization,angina,stroke,heart failure,or peripheral artery disease.Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk.Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction.RESULTS Of the total study participants(n=25516),5030 experienced a CVD event during a mean of 4.7 years follow-up.aTRH was associated with a 30%increase in risk of CVD compared to non-aTRH[hazards ratio(HR)=1.3,95%CI:1.19-1.42].Sex and age modified this relationship on both multiplicative and additive scales independently.Stratified by sex,aTRH was associated with a 64%increase in risk of CVD(HR=1.64,95%CI:1.43–1.88)in women,and a 13%increase in risk of CVD(HR=1.13,95%CI:1.01–1.27)in men.Stratified by age,aTRH had a stronger impact on the risk of CVD in participants aged<65(HR=1.53,95%CI:1.32–1.77)than it did in those aged≥65(HR=1.18,95%CI:1.05–1.32).Significant two-way interactions of sex and aTRH,and age and aTRH on risk of CVD were observed(P<0.05).The observed joint effect of aTRH and ages≥65 years(HR=1.85,95%CI:1.22–2.48)in males was less than what was expected for both additive and multiplicative models(HR=4.10,95%CI:3.63–4.57 and 4.88,95%CI:3.66–6.31),although three-way interaction of sex,age,and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance(P>0.05).CONCLUSION aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age.Further studies are warranted to test these mechanisms.

Pramipexole in Treatment Resistant Depression: A Case Review

Pramipexole is a dopamine agonist used in the treatment of Parkinson’s disease and Restless legs syndrome. Although off-label, the use of Pramipexole as an adjunct therapy in treatment resistant depression has recently been documented in the literature with promising results. We present a 75-year-old male with MDD who has failed trials of SSRIs, SNRIs, TCAs, SGA, TMS, Ketamine, and ECT who was initiated on Pramipexole. We discuss, based on existing literature, the probability of a favorable long-term response to Pramipexole and the potential side effects for our patient. We also highlight the need for future studies designed to test the efficacy of Pramipexole in geriatric patients with TRD.

Lipid metabolism analysis in esophageal cancer and associated drug discovery

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis.It is still being explored in depth due to its complex molecular mechanisms of occurrence and development.Lipids play a crucial role in cells by participating in energy supply,biofilm formation,and signal transduction processes,and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors.More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning,progress,and treatment resistance.The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism.Therefore,we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer,and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer,as well as its significance in exploring potential therapeutic targets and biomarkers.

Evolving landscape and novel treatments in, metastatic castrate-resistant prostate cancer

Treatment options for castrate-resistant prostate cancer （CRPC） have advanced in recent years and significantly improved the Outlook for patients with this aggressive and lethal disease. Further understanding of the biology＇of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor （AR） directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

Effect of Dietary Resistant Starch on Prevention and Treatment of Obesity-related Diseases and Its Possible Mechanisms

Overweight or obesity has become a serious public health problem in the world, scientists are concentrating their efforts on exploring novel ways to treat obesity. Nowadays, the availabilities of bariatric surgery and pharmacotherapy have enhanced obesity treatment, but it should has support from diet, physical exercise and lifestyle modification, especially the functional food. Resistant starch, an indigestible starch, has been studied for years for its beneficial effects on regulating blood glucose level and lipid metabolism. The aim of this review is to summarize the effect of resistant starch on weight loss and the possible mechanisms. According to numerous previous studies it could be concluded that resistant starch can reduce fat accumulation, enhance insulin sensitivity, regulate blood glucose level and lipid metabolism. Recent investigations have focused on the possible associations between resistant starch and incretins as well as gut microbiota. Resistant starch seems to be a promising dietary fiber for the prevention or treatment of obesity and its related diseases.

Crucial role of Anxa2 in cancer progression:highlights on its novel regulatory mechanism

Anxa2 is the most studied member of the calcium-mediated phospholipid-binding protein family annexins and is a biomarker in cancers.In this review,we listed clinical findings and confirmed the value of Anxa2 in early diagnosis and prognostic prediction due to its overexpression and adverse effect on the outcome in most tumors.Anxa2 plays a pivotal role in cancer cell proliferation,migration,invasion,metastasis,and treatment resistance.Improved understanding of its cancer-promoting function might make it an ideal target for cancer therapy.Here,we systematically summarized the mechanism of Anxa2 in regulating epithelialmesenchymal transition(EMT),cytoskeleton dynamicity,cell cycle,apoptosis,angiogenesis,and immunology by using various tumor models.These data emphasize the potential of Anxa2 for targeted intervention in tumors.Altering Anxa2 expression,neutralizing the cell surface Anxa2,or inhibiting its activation,such as through Tyr23 phosphorylation,could be considered based on the regulatory mechanism of Anxa2 in tumor progression.

Stroma-targeting strategies in pancreatic cancer:Past lessons,challenges and prospects

Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC.To date,combination chemotherapy remains the mainstay of treatment for most PDAC patients.Compared to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorterlived.Aside from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance.However,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes.These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression.The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune cells.This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease.Here,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.

Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis

Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations.Factors that stimulate cell fusion are inflammation and hypoxia.Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes,e.g.,reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition.There is now considerable in vitro,in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis.Of the many changes in cancer cells after hybridizing with leucocytes,it is notable that hybrids acquire resistance to chemo-and radiation therapy.One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization.Regardless of the mechanism of polyploid cell formation,it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive.Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis.In addition,we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.

Mechanisms and clinical implications in renal carcinoma resistance:narrative review of immune checkpoint inhibitors

Clear cell renal cell carcinoma(ccRCC)is the most common histological subtype of renal cell carcinoma.The prognosis for patients with ccRCC has improved over recent years with the use of combination therapies with an anti-programmed death-1(PD-1)backbone.This has enhanced the quality of life and life expectancy of patients with this disease.Unfortunately,not all patients benefit;eventually,most patients will develop resistance to therapy and progress.Recent molecular,biochemical,and immunological research has extensively researched antiangiogenic and immune-based treatment resistance mechanisms.This analysis offers an overview of the principles underpinning the resistance pathways related to immune checkpoint inhibitors(ICIs).Additionally,novel approaches to overcome resistance that may be considered for the trial context are discussed.

Postprocessing treatments to improve the laser damage resistance of fused silica optical surfaces and SiO_2 coatings

The combination of deep wet etching and a magneto-rheological finishing （MRF） process is investigated to simultaneously improve laser damage resistance of a fused-silica surface at 355 nm. The subsequently deposited SiO2 coatings are researched to clarify the impact of substrate finishing technology on the coatings. It is revealed that a deep removal proceeding from the single side or double side had a significant impact on the laser-induced damage threshold （LIDT） of the fused silica, especially for the rear surface. After the deep etching, the MRF process that followed does not actually increase the LIDT, but it does ameliorate the surface qualities without additional LIDT degradation. The combination guarantee both the integrity of the surface＇s finish and the laser damage resistance of the fused silica and subsequent SiO2 coatings.

Base excision repair accessory factors in senescence avoidance and resistance to treatments

Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.

Oncogenic MORC2 in cancer development and beyond

Microrchidia CW-type zinc finger 2(MORC2)is a member of the MORC superfamily of nuclear proteins.Growing evidence has shown that MORC2 not only participates in gene transcription and chromatin remodeling but also plays a key in human disease and tumor development by regulating the expression of downstream oncogenes or tumor suppressors.The present review provides an updated overview of MORC2 in the aspect of cancer hallmark and therapeutic resistance and summarizes its upstream regulators and downstream target genes.This systematic review may provide a favorable theoretical basis for emerging players of MORC2 in tumor development and new insight into the potential clinical application of basic science discoveries in the future.

Complex interplay between tumor microenvironment and cancer therapy

Tumor microenvironment （TME） is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

Effect of Sancaijiangtang on plasma nitric oxide and endothelin-1 levels in patients with type 2 diabetes mellitus and vascular dementia:a single-blind randomized controlled trial

OBJECTIVE: To observe the effect of Sancaijiangtang powders on plasma nitric oxide and endothelin-1 levels. We sought to identify the common pathological link and mechanism of action for Traditional Chinese medicine in type 2 diabetes mellitus and vascular dementia,and to explicate the material basis for treating the different diseases with the same method in Traditional Chinese Medicine.METHODS: In total,168 patients with type 2 diabetes mellitus and vascular dementia were enrolled in the study,and randomly divided into two groups by simple randomization. Patients in the treatment group received oral Sancaijiangtang powders with pioglitazone hydrochloride three times daily,while patients in the control group received pioglitazone hydrochloride alone. The treatment course was for12 weeks. Mini-mental state examinations(Chinese version) and Montreal Cognitive Assessments(Beijing version) were performed,and fasting plasma glucose,fasting insulin,hemoglobin A1 c,homeostasis model assessment of insulin resistance,plasma nitric oxide and endothelin-1 levels were measured before and after the treatment.RESULTS: The post-treatment levels for all measurements in both groups were better than pre-treatment levels(P < 0.05). The post-treatment levels for all measurements in the treatment group were better than the levels measured in the control group(P < 0.05).CONCLUSION: Type 2 diabetes mellitus and vascular dementia have common pathological mechanisms for insulin resistance and endothelium dysfunction. Sancaijiangtang powders could improve the release of nitric oxide and inhibit the secretion of endothelin-1. Therefore,the material basis exists for treating the different diseases with the same method in Traditional Chinese Medicine.

Effects of Cr Content on the Microstructure and Properties of 26Cr–3.5Mo–2Ni and 29Cr–3.5Mo–2Ni Super Ferritic Stainless Steels

By using scanning electron microscopy, energy-dispersive spectrometry, X-ray diffraction, strength and hardness measurements, the microstructure, precipitation, mechanical properties, and corrosion resis- tance have been investigated for two super ferritic stainless steels, 26Cr-3.SMo-2Ni and 29Cr-3.5Mo- 2Ni, with the aim to consider the effect of Cr content. The results showed that with the addition of Cr content, the recrystallization temperature was increased; the precipitation of Laves and Sigma （o） phases was promoted and the mechanical properties of super ferritic stainless steel were modified. Further- more, the pitting corrosion resistance and corrosion resistance to H2SO4 of the two super ferritic stainless steels were improved. In addition, suitable annealing processing is a key factor to maintain integrated performance by optimizing microstructure and removing detrimental precipitation phases.

Effect of rhenium on the microstructure and mechanical behavior of Fe–2.25Cr–1.6W–0.25V-0.1C bainitic steels

A new ferritic creep resistant steel has been developed by eliminating Nb and adding 1.5 mass % Re to a ferritic steel grade T/P23 with the aim of enhancing its mechanical properties at high temperature.Cast ingots of both steels, new grade and ASTM T/P 23, were hot rolled at 900℃ and then submitted to a thermal treatment consisting of solubilization at 1050℃ and tempering at 700℃. Tempered bainitic microstructures obtained contain second phases reinforcing carbide particles, mainly M_6C and M_（23）C_6 at the boundaries of both, prior austenite grains and bainitic ferrite laths, as well as MC within the grains. Mechanical properties at temperatures ranging from 540 to 600℃ were studied by strain-ratechange tests in compression at strain rates between 10^（-7） and 10^（-4）s^（-1）. These tests showed high stress exponents（n ≥ 20） and activation energies（Q ≈ 400 k J/mol） for both alloys, which were associated with a dislocation movement mechanism with a strong interaction between dislocations and precipitates. On the other hand, a creep exponent of 5 was derived for the stress dependence of minimum creep rate from conventional-type creep tests at 600℃. Although this stress exponent is usually related to a dislocation climb controlled creep mechanism, remarkable microstructural degradation observed with increasing creep time makes difficult to elucidate the true deformation mechanism controlling creep.