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Cancer stem cells (CSCs) are a class of cells with self-renewal, differentiation, and tumorigenic potential in tumors. It is currently believed that the resistance of CSCs to chemotherapy and radiotherapy is an important cause of tumor recurrence and metastasis. Researchers have found that related factors in many signaling pathways endow CSCs with the ability to adapt to changes in the microenvironment, including inflammatory factors, hypoxia, low pH, and a lack of nutrients. In recent years, the mechanism of CSCs' resistance to therapy has been studied, mainly including the drug efflux mediated by the ATP-binding cassette transporter, the effect of aldehyde dehydrogenase 1 (ALDH1) activity on tumor stem cells, the enhancement of DNA damage repair and degradation of reactive oxygen species, autophagy, activation of development-related pathways, stimulation of the microenvironment, and EMT. The targeting strategies for CSCs include targeting signaling pathway inhibitors, targeting multidrug resistance, DNA damage repair, ALDH, targeting the tumor microenvironment, immunotherapy, etc. In this review, the research progress in CSCs treatment resistance and related treatment strategies was reviewed.
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@#Oestrogen receptor (ER)-positive breast cancer is one of the common forms of breast cancer affecting women worldwide. ER-positive breast cancer patients are subjected to antioestrogen therapy such as selective oestrogen receptor modulator (SERM) and aromatase inhibitors (AIs). Recently, the emergence of resistance to anti-oestrogen treatment is under intensive focus. The different mechanisms postulated to explain the occurrence of resistance in ER-positive breast cancer treatment include the loss of ER function and the crosstalk between signalling pathways in cancer cells. Recent literature highlighted that the cholesterol biosynthesis pathway acts as a novel mechanism underlying resistance to oestrogen deprivation. The present study aimed to highlight the role of cholesterol biosynthesis in anti-oestrogen treatment resistance, putatively suggesting an alternative plant-based treatment using andrographolide from Andrographis paniculata. The hypolipidaemic effect of andrographolide can be utilised to prevent the resistance in the treatment of ER-positive breast cancer contributed by cholesterol biosynthesis.
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Objective: To investigate the role and mechanism of glutamic-pyruvic transaminase 2 (GPT2) on cisplatin resistance in gastric cancer. Methods:The Kaplan Meier-Plotter database was used to analyze the relationship between GPT2 expression and poor prognosis of gastric cancer. The expressions of GPT2 in gastric cancer cells and tissues were detected by quantitative real-time PCR (qPCR), Western blotting and immunohistochemistry (IHC). The cytotoxicity of cisplatin at different concentrations to human gastric cancer cells and normal gastric epithelial cells was detected by CCK-8 assay. GPT2 overexpression and knockdown cell lines were constructed in cisplatin sensitive MKN28 cells and insensitive MKN45 cells, respectively. CCK-8 assay, colony formation assay and Western blotting were performed to evaluate the cellular cytotoxicity, stemness of cancer cells and the changes of key proteins in stemness-related signaling pathways in GPT2 overexpression and knockdown cell lines, respectively. Results:The high expression of GPT2 was negatively correlated with the survival of gastric cancer patients. Gastric cancer cells with high expression of GPT2 were resistant to cisplatin, while cells with low expression of GPT2 were sensitive to cisplatin. Overexpression of GPT2 could decrease the cell sensitivity to cisplatin, nevertheless knockdown of GPT2 could increase the cell sensitivity to cisplatin. Meanwhile, the further study revealed that overexpression of GPT2 could activate the extracellular regulated protein kinases (ERK) signaling pathway, up-regulate the expression of SRY-box 2 (SOX2) and Nanog homeobox (NANOG), and enhance the ability of colony formation, while knockdown of GPT2 could inhibit ERK signaling pathway, reduce the expression of SOX2 and NANOG, and suppress the ability of colony formation. Conclusion:GPT2 expression are related to the sensitivity of cisplatin treatment. Overexpression of GPT2 can increase the resistance of gastric cancer to cisplatin treatment by activating ERK signaling pathway and up-regulating the expression of SOX2 and NANOG.
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Background: The efficacy of traditional treatment for irritable bowel syndrome (IBS) is limited. Some small case series published abroad showed that fecal microbiota transplantation (FMT) is effective for treatment-resistant IBS, but studies investigating the effect of FMT on IBS refractory to conventional therapy are rare in China. Aims: To observe the efficacy and safety of FMT in patients with IBS refractory to conventional therapy. Methods: Nineteen inpatients with IBS (including 15 cases of IBS with diarrhea and 4 cases of IBS unclassifiable) at the First Affiliated Hospital of Guangdong Pharmaceutical University who were refractory to conventional treatment for more than 6 months were enrolled in this study. Fecal microbiota was transplanted through colonic or middle digestive tract transendoscopic enteral tubing (TET). The clinical efficacy and safety were evaluated after 1 month and 6 months of treatment. Results: Each IBS patient received 2-4 courses of treatment (totally 186 FMT procedures). The mean value of Bristol stool form scale was 6.00±0.67 before FMT treatment, and decreased to 4.58±0.61 and 4.32±0.58 after 1 month and 6 months of treatment, respectively (P0.05). The most common adverse effects were transient diarrhea, distension and abdominal pain during the hospitalization. During the 6-month follow-up, no adverse effects and pathogen-related diseases were observed. Conclusions: FMT is effective for the treatment of IBS patients who are refractory to conventional therapy. The adverse effects are mild and transient.
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En este artículo describiremos brevemente ciertos pacientes que consultan por cuadros psiquiátricos agudos y que además sufren de difusión de identidad. Estos pacientes ofrecen dificultades importantes a su propio tratamiento porque tienden a no persistir en una tarea, no cuidar de sí mismos, no confiar en las personas y a no recuperarse de las fallas de mentalización que puedan tener en sus relaciones interpersonales, produciendo graves complicaciones en el proceso terapéutico. Describiremos el Programa de Intervención Psicoeducativa y Control Farmacológico en Grupo que hemos implementado en el Instituto Psiquiátrico José Horwitz Barak para manejar de mejor forma las dificultades terapéuticas que estos pacientes ofrecen.
In this article we will briefly describe certain patients who consult for acute psychiatric symptoms and who also suffer from identity diffusion. These patients offer significant difficulties to their own treatment because they tend not to persist in a task, do not take care of themselves, do not trust people and do not recover from the mentalization failures they may have in their interpersonal relationships, producing serious complications in the therapeutic process. We will describe the Program of Psychoeducative Intervention and Pharmacological Control in Group that we have implemented in the José Horwitz Barak Psychiatric Institute to better manage the therapeutic difficulties that these patients offer.
Subject(s)
Humans , Personality Disorders/psychology , Personality Disorders/therapy , Personality Disorders/drug therapy , Psychotherapy, Group , Patient Education as Topic , Treatment Refusal , Patient ComplianceABSTRACT
Introducción. El asma grave representa 5-7% del total de asmáticos. La OMS propuso un protocolo de seguimiento para categorizarlos como asma grave resistente al tratamiento (AGRT) o asma grave de difícil control (AGDC). Objetivo. Analizar las características clínicas, funcionales y terapéuticas de pacientes con AGRT o AGDC. Métodos. Estudio transversal, observacional y analítico para evaluar el diagnóstico, grado de control (clínico y funcional), comorbilidades, adherencia al tratamiento, técnica inhalatoria y factores ambientales en pacientes con asma grave. Resultados. Se incluyeron 69 pacientes: AGRT (n= 33) y AGDC (n= 36). El 100% del grupo con AGRT fue hospitalizado previamente por asma vs. 87,8% del grupo con AGDC (p= 0,03). El 63% del grupo AGRT requirió cuidados intensivos (UCI)), 82%, asistencia ventilatoria y uno fue traqueostomizado. En el AGDC, 54% requirió internación en la UCI , y 33%, asistencia ventilatoria (p= 0,03). La espirometría basal fue normal en el AGDC; se observó incapacidad ventilatoria obstructiva leve en el AGRT (p= 0,009). En el AGDC, hubo menor cumplimiento del tratamiento (p= 0,01). Se requirieron dosis mayores de corticoides inhalados en AGRT (p= 0,0001). Omalizumab fue indicado en AGRT (p= 0,0001). A los 6 meses de seguimiento, más del 75% de los niños en ambos grupos presentó asma controlada. Conclusiones. Se observó significativa falta de adherencia al tratamiento en el grupo AGDC. Se redujeron las dosis de tratamiento en este grupo. Se logró controlar la enfermedad en un alto porcentaje de niños con AGRT y AGDC.
Introduction. Severe asthma accounts for 5-7% of all asthma cases. The World Health Organization proposed a follow-up protocol to classify cases into severe, treatment-resistant asthma (STRA) or severe, difficult-to-control asthma (SDCA). Objective. To analyze the clinical, functional, and therapeutic characteristics of patients with STRA or SDCA. Methods. Cross-sectional, observational, and analytical study to assess the diagnosis, the extent of control (clinical and functional), comorbidities, treatment adherence, inhalation technique, and environmental factors in patients with severe asthma. Results. A total of 69 patients were included: STRA (n= 33) and SDCA (n= 36). In the group with STRA, 100% of patients had been previously hospitalized due to asthma compared to 87.8% in the group with SDCA (p= 0.03). In the group with STRA, 63% required admission to the intensive care unit (ICU); 82%, ventilatory support; and 1 patient, tracheostomy. In the group with SDCA, 54% required admission to the ICU; and 33%, ventilatory support (p= 0.03). The baseline spirometry was normal in the SDCA group; a mild obstructive ventilatory defect was observed in the STRA group (p= 0.009). In the SDCA group, treatment adherence was lower (p= 0.01). Higher inhaled corticosteroid doses were required in the STRA group (p= 0.0001). Omalizumab was indicated in the case of STRA (p= 0.0001). After 6 months of follow-up, more than 75% of children in both groups achieved asthma control. Conclusions. A significant lack of treatment adherence was observed in the SDCA group. In this group, treatment doses were reduced. Asthma was controlled in a high percentage of children with STRA and SDCA.
Subject(s)
Humans , Male , Female , Child , Adolescent , Asthma/diagnosis , Asthma/etiology , Asthma/therapy , Severity of Illness Index , Asthma/complications , Clinical Protocols , Cross-Sectional Studies , Follow-Up Studies , Patient Compliance , Treatment Outcome , Combined Modality Therapy , HospitalizationABSTRACT
OBJECTIVE: Continuation-maintenance electroconvulsive therapy (C/M-ECT) is used to prevent relapse or recurrence in patients with severe mental illnesses. We aimed to investigate the effect of C/M-ECT on reducing hospital re-admissions in patients with treatment-resistant schizophrenia. METHODS: We applied a mirror-image design by retrospectively examining re-hospitalization rates of 18 patients with schizophrenia spectrum disorders. We compared the numbers of psychiatric admissions during the actual period over which C/M-ECT was administered with the same period prior to the beginning of C/M-ECT. RESULTS: The number of psychiatric admissions was reduced significantly during C/M-ECT (0.33±0.77) compared with that of the same period prior to C/M-ECT (2.67±1.33) (Wilcoxon signed rank Z=−3.663; p < 0.001). CONCLUSION: This finding shows that C/M-ECT augmentation could successfully reduce the re-hospitalization rates in patients with treatment-resistant schizophrenia.
Subject(s)
Humans , Electroconvulsive Therapy , Hospitalization , Recurrence , Retrospective Studies , SchizophreniaABSTRACT
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.
Subject(s)
Humans , Antineoplastic Agents , Pharmacology , Drug Resistance , Neoplasm Staging , Neoplasms , Drug Therapy , Pathology , Treatment Outcome , Tumor Microenvironment , PhysiologyABSTRACT
Hepatocellular carcinoma (HCC) has the characteristics of high malignancy and poor prognosis.Liver transplantation and hepatectomy are applied in a small portion of patients with localized disease.Due to the hidden onset,HCC is usually diagnosed at an intermediate-advanced stage or with advancing cirrhosis.In most cases,various non-operative treatments are applied,including transarterial chemoembolization (TACE),local ablation,radiotherapy and molecular targeted drugs.The therapeutic effect of non-surgical treatments is not always ideal because the incidence of recurrence and metastasis after treatment is high.It also may be associated with treatment resistance of HCC to non-operative treatments.Optimizing the current management schemes has great significance in improving patients' quality of life and prolonging their survival.
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PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.
Subject(s)
Adult , Humans , Brain , Cell Line , Genes, Homeobox , Glioblastoma , In Vitro Techniques , Microarray Analysis , Prognosis , RadiotherapyABSTRACT
Treatment-resistant depression (TRD) is a major public health problem. It is estimated that about 30% of patients with major depressive disorder do not show substantial clinical improvement to somatic or psychosocial treatment. Most of studies for TRD have focused on the subjects already known as TRD. Patients with unipolar depressive episodes that do not respond satisfactorily to numerous sequential treatment regimens were included in the TRD studies. Such post hoc experimental design can be regarded only as consequences of having TRD, rather than as causal risk factors for it. Although informative, data derived from such studies often do not allow a distinction to be made between cause and effect. So, we should shift paradigm toward examining the risk for developing TRD in untreated depressed patients. To deal with this problem, untreated depressed patients should be enrolled in the study to identify biological markers for treatment resistance. The peripheral or central biological markers should be explored before starting treatment. Subsequent systematic administration of treatments with appropriate monitoring in the subjects can determine the risk for developing treatment resistance in untreated individuals. Such information could give a cue to improve the initial diagnosis and provide more effective treatment for TRD.
Subject(s)
Humans , Biomarkers , Cues , Depression , Depressive Disorder, Major , Depressive Disorder, Treatment-Resistant , Diagnosis , Neuroimaging , Public Health , Research Design , Risk FactorsABSTRACT
While it has been reported previously that the loudness dependence of auditory evoked potentials (LDAEP) is a putative biological marker or a predictor of treatment response, there have been few studies of LDAEP in bipolar disorder. However, a recent study by Park and colleagues raised the possibility that the LDAEP could be useful as a biological marker of bipolar disorder. They found that the LDAEP was significantly higher in normal controls than in patients with either bipolar disorder or schizophrenia. Lee and colleagues also examined the LDAEP in bipolar disorder and normal controls, and found that it differed according to the bipolar phase, being significantly higher in cases of euthymic bipolar disorder, bipolar depression, and bipolar mania. With regard to treatment response, early clinical findings were that a higher LDAEP and a stronger intensity dependence of visual evoked potentials were related to a favorable response to lithium treatment. Juckel and colleagues recently demonstrated that the pretreatment LDAEP could be a predictor of successful prophylactic lithium treatment. The present article reviews the literature in order to determine whether the LDAEP can be used as a biological marker or a predictor of treatment response in patients with bipolar disorder and of manic switch or treatment resistance in patients with major depressive episode(s).
Subject(s)
Humans , Biomarkers , Bipolar Disorder , Evoked Potentials, Auditory , Evoked Potentials, Visual , LithiumABSTRACT
OBJECTIVE: Major Depressive Disorder (MDD) is a debilitating condition with a marked social impact. The impact of MDD and Treatment-Resistant Depression (TRD+) within the Brazilian health system is largely unknown. The goal of this study was to compare resource utilization and costs of care for treatment-resistant MDD relative to non-treatment-resistant depression (TRD-). METHODS: We retrospectively analyzed the records of 212 patients who had been diagnosed with MDD according to the ICD-10 criteria. Specific criteria were used to identify patients with TRD+. Resource utilization was estimated, and the consumption of medication was annualized. We obtained information on medical visits, procedures, hospitalizations, emergency department visits and medication use related or not to MDD. RESULTS: The sample consisted of 90 TRD+ and 122 TRD- patients. TRD+ patients used significantly more resources from the psychiatric service, but not from non-psychiatric clinics, compared to TRD- patients. Furthermore, TRD+ patients were significantly more likely to require hospitalizations. Overall, TRD+ patients imposed significantly higher (81.5%) annual costs compared to TRD- patients (R$ 5,520.85; US$ 3,075.34 vs. R$ 3,042.14; US$ 1,694.60). These findings demonstrate the burden of MDD, and especially of TRD+ patients, to the tertiary public health system. Our study should raise awareness of the impact of TRD+ and should be considered by policy makers when implementing public mental health initiatives.
OBJETIVO: O Transtorno Depressivo Maior (TDM) é uma condição debilitante com um forte impacto social. O impacto do TDM e Depressão Resistente ao Tratamento (DRT+) no sistema de saúde brasileiro é praticamente desconhecido. Nosso objetivo é comparar a utilização de recursos e custos dos cuidados para o tratamento de DRT+ em relação ao TDM não resistente (DRT-). MÉTODOS: Foram analisados retrospectivamente os prontuários de 212 pacientes diagnosticados com TDM segundo a CID-10. Critérios específicos foram utilizados para identificar pacientes com DRT+. A utilização dos recursos foi estimada e consumo de medicamentos foram anualizados. Foram obtidas informações sobre consultas, procedimentos, internações, atendimentos no serviço de emergência e uso de medicação relacionada ou não ao TDM. RESULTADOS: A amostra foi composta de 90 pacientes DRT+ e 122 DRT-. Pacientes DRT+ utilizaram significativamente mais recursos do serviço de psiquiatria, mas não em clínicas não psiquiátricas, em relação a DRT-. Eles eram significativamente mais propensos a exigir internações. Pacientes DRT+ apresentaram um custo direto anual significativamente maior (81,5%) do que pacientes com depressão não resistente (R$ 5.520,85; US$ 3.075,34 contra R$ 3.042,14, US$ 1.694,60). Estes resultados demonstram o impacto do TDM, principalmente da DRT+ ao sistema de saúde público terciário. Nosso estudo deve aumentar a sensibilização para o impacto da DRT + e deve ser considerado pelos formuladores de políticas públicas na implementação de iniciativas de saúde mental.
Subject(s)
Female , Humans , Male , Middle Aged , Depressive Disorder, Major/economics , Depressive Disorder, Major/therapy , Depressive Disorder, Treatment-Resistant/economics , Health Care Costs , Health Resources/economics , Brazil , Costs and Cost Analysis , Health Resources , Hospitalization/economics , Length of Stay/economics , Retrospective StudiesABSTRACT
El trastorno obsesivo-compulsivo (TOC) constituye una enfermedad crónica incapacitante con profundas implicancias para el funcionamiento social. Todas las esferas vitales de los pacientes que padecen este trastorno se ven afectadas. El tratamiento con inhibidores de la recaptación de serotonina es efectivo en el 40 a 60 de los pacientes con TOC, transformando a un importante porcentaje de pacientes en no respondedores al tratamiento. Además, entre aquellos pacientes que responden, a menudo no se observa una remisión completa, la cual debería constituir el objetivo de todo tratamiento del TOC. Se describe como pacientes con TOC refractarios al tratamiento a aquellos que han recibido tratamientos adecuados de primera línea sin lograrse una respuesta satisfactoria. Se revisan en este artículo diferentes estrategias terapéuticas, convencionales y alternativas, para el abordaje de este grupo de pacientes.
Obsessive-compulsive disorder (OCD) is a chronic disabling disease with profound implications for social functioning. OCD affects all spheres of functioning of patients who suffer the disorder. Treatment with serotonin reuptake inhibitors is effective in 40 to 60 of patients with OCD, but a large percentage of patients are non responsive to treatment. Those patients who do respond often do not fully remit, which should be the standard goal of treatment in OCD. Treatment refractory patients with OCD are those who undergo adequate trials of first-line therapies without a satisfactory response. Conventional treatment and alternative treatment options for this population are reviewed.
Subject(s)
Humans , Treatment Failure , Obsessive-Compulsive Disorder/therapy , Antipsychotic Agents/therapeutic use , Obsessive-Compulsive Disorder/drug therapyABSTRACT
There have been considerable advances in our understanding of the neurobiology and the treatment of obsessive-compulsive disorder (OCD). However, it seems that many patients with OCD are not met with proper treatment, and even the patients who receive sufficient therapy the response rate is not high. This paper reviews the pharmacological treatments of OCD with special focus on therapeutic options for treatment resistance cases. In treating a resistant case, the clinical characteristics including comorbid conditions of the patient should be reevaluated. Through until recently, there has been no standarized guideline to treat resistance cases and much is up to clinician's preference, but thoughtful selection and combination of drugs with optimized psychosocial approach may improve the response rate. We propose an integrative therapy model for treatment resistant OCD to emphasize the need for the expansion of treatment resources. Treatment resistant OCD deserves more clinical and socioeconomic attentions and needs further research for management.
Subject(s)
Humans , Attention , Drug Therapy , Neurobiology , Obsessive-Compulsive DisorderABSTRACT
Whenever a clinician manages the patients with depression, he may meet various prolems that make it difficult to treat them. Even though he has good skills and knowledge abut depression, some barriers will be appear during his practice. In general, the difficulties in treating depression are treatment-resistance, adverse effects of antidepressants, pregnancy in female patients, comorbid medical conditions, poor compliance, drug-drug interactions, and so on, which are related with pharmacological treatments. Here, only the two of them, the treatment-resistant depression and difficult problems concerned with pregnancy, were discussed. Some level of treatment resistance is the norm rather tnan the exception. As the treatment failure stems from inadequate treatment, it is important that the clinician should prescribe medications with sufficient doseage and adequate duration. And to overcome the treatment resistant depression the polypharmacy is necessary, in that case, the side effects and toxicities should be explored and managed immediately. So the clinician have to learn more about the pharmacokinetic and pharmacodynamic mechanisms of each drugs used in treatment of depression. When the risk of the fetus by the exposure is higher than the risk of untreated maternal psychiatric disorder, psychotropic medications should be used durig pregnancy. Women who are maintained on psychotropics and become pregnant, as well as women with the new onset of psychiatric symptoms durig pregnancy, should be carefully reassessed. However, data concerning the potential risk of long-term behavioral changes folowing prenatal exposure to psychotropics is rare, so further longitudinal follow-up studies are needed.