In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.

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Ferroptosis, necroptosis, and pyroptosis in anticancer immunity

Objective
There is a high prevalence of problematic online gaming in adolescents with attention deficit hyperactivity disorder (ADHD). In the current study, we compared the effectiveness of atomoxetine (ATM) and methylphenidate (MPH) on problematic online gaming in adolescents with ADHD.

Methods
We recruited 86 adolescents diagnosed with ADHD together with Internet gaming disorder. These participants were divided into two treatment groups: 44 participants were treated with MPH for 12 weeks, and 42 participants were treated with ATM for 12 weeks.

Results
During the 3-month study period, the MPH group showed greater improvement in Korean ADHD rating scale scores than the ATM group. The ATM group showed greater improvement in Child Depression Inventory scores than the MPH group. However, Young Internet Addiction Scale and Behavioral Inhibition & Activation Scales score changes did not differ significantly between the MPH and ATM groups. In both groups, changes in Young Internet Addiction Scale scores were positively correlated with the changes in Behavioral Inhibition & Activation Scales scores.

Conclusions
Both MPH and ATM reduced the severity of Internet gaming disorder symptoms, and this reduction was correlated with impulsivity reduction, which also resulted from both ADHD medications. These findings suggest impulsivity plays a critical role in the development of problematic online gaming.

Effectiveness of atomoxetine and methylphenidate for problematic online gaming in adolescents with attention deficit hyperactivity disorder

In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune "cold" tumors into "hot" tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy. 

/pdf/autophagy-ferroptosis-pyroptosis-and-necroptosis-in-tumor-191xb91c.pdf

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

/pdf/insulin-receptor-isoforms-in-cancer-4ypjyn02sy.pdf

Insulin Receptor Isoforms in Cancer

Endometrial cancer is one of the most common cancers of the female reproductive system. Although surgery, radiotherapy, chemotherapy, and hormone therapy can significantly improve the survival of patients, the treatment of patients with very early lesions and a strong desire to retain reproductive function or late recurrence is still in the early stages. Metabolic syndrome (MS) is a clustering of at least three of the five following medical conditions: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Obesity, diabetes and hypertension often coexist in patients with endometrial cancer, which increases the risk of endometrial cancer, also known as the "triple syndrome of endometrial cancer." In recent years, epidemiological and clinical studies have found that MS associated with metabolic diseases is closely related to the incidence of endometrial cancer. However, the key molecular mechanisms underlying the induction of endometrial cancer by MS have not been elucidated to date. Characterizing the tumor metabolism microenvironment will be advantageous for achieving a comprehensive view of the molecular mechanism of metabolic syndrome associated with endometrial cancer and for providing a new target for the treatment of endometrial cancer. This review focuses on recent advances in determining the role of metabolic syndrome-related factors and mechanisms in the pathogenesis of endometrial cancer. We suggest that interfering with the tumor metabolic microenvironment-related molecular signals may inhibit the occurrence of endometrial cancer.

/pdf/the-role-of-metabolic-syndrome-in-endometrial-cancer-a-3orwlebnqv.pdf

The Role of Metabolic Syndrome in Endometrial Cancer: A Review

Background Metformin is widely used for management of Type 2 Diabetes Mellitus (T2DM). Recently growing evidences have shown its anti-cancer effects. The results are mainly from observational studies and thus few information is available concerning the mechanisms of action. Method This paper reviews recent available evidences for anti-cancer effects of metformin. The effects of metformin in specific cancers including colorectal, prostate, pancreatic, renal, cervical, endometrial, gastric, lung, breast, and ovarian cancer are reviewed. Results Adenosine Monophosphate (AMP)-Activated Protein Kinase (AMPK) plays an important role in mechanism of action of metformin. The anti-cancer mechanisms of metformin include direct and indirect effects. The direct effects of metformin include AMPK-independent and AMPK-dependent effects whereas decrease in glucose level, hyperinsulinemia, and Insulin-like Growth Factor 1 (IGF-1) level are considered its indirect effects. Metformin also decreases both pro-inflammatory cytokines and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF- κB) and improves the immune response to cancer cells. Conclusion Although the results of recent trials confirm the efficacy of metformin in prevention and treatment of different cancers, the evidences are not adequate enough.

Anti-cancer Effects of Metformin: Recent Evidences for its Role in Prevention and Treatment of Cancer

Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children which manifests with hyperactivity, impulsivity, and/or inattention. Several drugs are used in treatment of ADHD. Stimulants, atomoxetine, anti-depressants, and bupropion are common medications used in the treatment of ADHD. Stimulants are widely used as the first line treatment in children with ADHD. Their mechanism of action is the release of dopamine and norepinephrine in central nervous system. Methylphenidate is the most common stimulant used for the treatment of ADHD. Methylphenidate significantly reduces ADHD symptoms in children both at home and school and improves their social skills. Methylphenidate is safe in healthy children and has shown to have no cardiac side effects in these patients. Other medications include: Atomoxetine, Amphetamines, Clonidine, Melatonin, and anti-depressants. Effects, side effects, and mechanism of action these drugs have been discussed in this paper.

Psychopharmacology of Attention-Deficit Hyperactivity Disorder: Effects and Side Effects.

Background: Migraine is one of the most common etiologies for headache. This very common neurological disorder has a significant impact on patients' quality of life. The aim of the current study is to evaluate the prevalence of migraine among medical students in the Hormozgan University of Medical Sciences (HUMS). Methods: A total of350 medical students wer e enrolled in our descriptive study. Data were collected using the standard questionnaire of the International Headache Association. The data were analyzed by SPSS 20.0 software using descriptive statistics, Chi -Square, and Independent Samples T -Test. A P-value of"e0.05 was considered statistically significant, since most public health professionals use this value as a standard. Results:Among the medical students in our study, 24.6% had experienced frequent, severe headaches. The underlying causes of the headaches were diagnosed in 19.8% of the students. The prevalence of migraine in our study was 16.3% (mean age=21.28±2.71years). The prevalence varied by gender, and it was greater among male students. Conclusion:Our findings indicated that there was a high prevale nce of migraine among the medical students in our study, and these findings were consistent with those of previous studies in Iran and other countries.

/pdf/prevalence-of-and-factors-associated-with-migraine-in-2xcomusdnx.pdf

Prevalence of and Factors Associated with Migraine in Medical Students at BandarAbbas, Southern Iran, in 2012.

Diabetes mellitus (DM) is a chronic disease with long-term complications. Glycemic control is an importantpart in management of DM. The first line in treatment of type 2 DM (T2DM) is diet and life style change. Metformin isthe first choice of medication in T2DM patients. Sulfonylureas have high risk of hypoglycemia. Glinides are associatedwith lower risk of hypoglycemia in comparison to sulfonylureas. Also, α-glucosidase inhibitors decrease the polysaccharides’digestion in small intestine and are less effective in comparison to metformin and sulfonylureas in loweringhemoglobin A1c (HbA1c). These have no risk for hypoglycemia, but gastrointestinal symptoms are common. Thiazolidinedionesare known as insulin sensitizers and are effective for a longer duration in comparison to sulfonylureas,however, have side effects such as fluid retention, edema and heart failure. Incretin mimetics including exenatide andliraglutide act through increase in insulin secretion by pancreatic beta cells, in a glucose-dependent manner. Therefore,these are associated with no risk of hypoglycemia. Pramlintide is an amylin agonist which is also effective in loweringpostprandial blood glucose. Sitagliptin and vildagliptin are dipeptidyl peptidase-4 inhibitors and have no risk of hypoglycemiawhen used as monotherapy. Canagliflozin and dapagliflozin decrease blood glucose level by increasing urinaryglucose excretion and are associated with weight loss.

Challenges Related to Glycemic Control in Type 2 Diabetes Mellitus Patients.

Introduction: Tuberculosis (TB) is one of the most important causes of mortality and morbidity in developing countries and is responsible for about 25% of all preventable deaths. Therefore we aimed to assess the knowledge and attitude towards TB among guidance school in rural areas of Bandarabbas in 2010.
Methods and Materials: In this cross sectional study our samples were selected using cluster sampling. All of the 81 participants completed a standard TB attitude and knowledge questionnaire. The questionnaire included 16 questions concerning knowledge and 9 questions regarding attitude towards TB. Data was entered the SPSS 13 software and analyzed using the descriptive statistics.
Results: Eighty one students were enrolled in this study. Among them, 41 (50.6%) were male and 40 (49.4%) were female. The mean age of the participants was 12.67 ± 1.5 years. Almost all of the participants knew the signs and symptoms, ways of transmission and prevention methods of TB. Most of the students, 48 (59.3%), had received TB related information by television.
Conclusions: Our results demonstrated that knowledge toward TB is high among these students. The most important source of information of the students was television, therefore we suggest to improve the quality and number of television's educational programs in order to increase the students’ knowledge, introduce the TB support centers, and changing the attitude and behavior of health staff.

http://idrc.resv.hums.ac.ir/uploads/57_564_97_14.pdf

Maryam Yazdanparast

Papers

Anti-cancer Effects of Metformin: Recent Evidences for its Role in Prevention and Treatment of Cancer

Psychopharmacology of Attention-Deficit Hyperactivity Disorder: Effects and Side Effects.

Prevalence of and Factors Associated with Migraine in Medical Students at BandarAbbas, Southern Iran, in 2012.

Challenges Related to Glycemic Control in Type 2 Diabetes Mellitus Patients.

Knowledge and attitudes towards tuberculosis among secondary school students in rural areas in Hormozgan, Southern Iran