The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management.

Historical advances in the care of patients with non-Hodgkin lymphoma (NHL) have been restricted largely to patients with B-cell lymphoma. The peripheral T-cell lymphomas (PTCLs), which are rare and heterogeneous in nature, have yet to experience the same degree of improvement in outcome over the past 20 to 30 years. It is estimated that there are approximately 80,000 and 14,000 cases, respectively, of NHL and Hodgkin lymphoma per year in the United States. As a subgroup of NHL, the PTCLs account for 6% to 10% of all cases of NHL, making them exceedingly rare. In addition, the World Health Organization 2017 classification describes 29 distinct subtypes of PTCL. This intrinsic diversity, coupled with its rarity, has stymied progress in the disease. In addition, most subtypes carry an inferior prognosis compared with their B-cell counterparts, an outcome largely attributed to the fact that most treatment paradigms for patients with PTCL have been derived from B-cell neoplasms, a radically different disease. In fact, the first drug ever approved for patients with PTCL was approved only a decade ago. The plethora of recent drug approvals in PTCL, coupled with a deeper understanding of the molecular pathogenesis of the disease, has stimulated the field to pursue new avenues of research that are now largely predicated on the development of novel, targeted small molecules, which include a host of epigenetic modifiers and biologics. There is an expectation these advances may begin to favorably challenge the chemotherapy paradigms that have been used in the T-cell malignancies.

A Look Into the Future: Are We Ready for an Approved Therapy in Celiac Disease?

As it appears that we are currently at the cusp of an era in which drugs that are new, re-purposed, or "supplements" will be introduced to the management of celiac disease, we need to reflect on whether the framework is set for celiac disease to be treated increasingly with pharmaceuticals as well as diet. This refers to reflecting on the rigor of current diagnostic practices; the limitations of the current standard of care, which is a gluten-free diet; and that we lack objective markers of disease severity. Investigating these issues will help us to identify gaps in technology and practices that could be critical for selecting patients with a well-defined need for an improved or alternative treatment. Both aspects, circumscribed limitations of the gluten-free diet and diagnostics helping to define celiac disease target groups, together with the guiding requirements by the responsible regulatory authorities, will contribute to defining the subgroups of patients with confirmed celiac disease eligible for distinct pharmacologic strategies. Because many patients with celiac disease are diagnosed in childhood, these aspects need to be differentially discussed for the pediatric setting. In this perspective, we aimed to describe these contextual issues and then looked ahead to the future. What might be the major challenges in celiac disease clinics in the coming years once drugs are an option alongside diet? And what will be the future objectives for researchers who further decipher the mucosal immunology of celiac disease? Speculating on the answers to these questions is as stimulating as it is fascinating to be part of this turning point.

Azacitidine treatment for myeloid leukemia associated with Down syndrome: A nationwide retrospective study in Japan.

Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.

Broader Perspective on Atherosclerosis-Selected Risk Factors, Biomarkers, and Therapeutic Approach.

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading cause of mortality worldwide. At its core lies a progressive process of atherosclerosis, influenced by multiple factors. Among them, lifestyle-related factors are highlighted, with inadequate diet being one of the foremost, alongside factors such as cigarette smoking, low physical activity, and sleep deprivation. Another substantial group of risk factors comprises comorbidities. Amongst others, conditions such as hypertension, diabetes mellitus (DM), chronic kidney disease (CKD), or familial hypercholesterolemia (FH) are included here. Extremely significant in the context of halting progression is counteracting the mentioned risk factors, including through treatment of the underlying disease. What is more, in recent years, there has been increasing attention paid to perceiving atherosclerosis as an inflammation-related disease. Consequently, efforts are directed towards exploring new anti-inflammatory medications to limit ASCVD progression. Simultaneously, research is underway to identify biomarkers capable of providing insights into the ongoing process of atherosclerotic plaque formation. The aim of this study is to provide a broader perspective on ASCVD, particularly focusing on its characteristics, traditional and novel treatment methods, and biomarkers that can facilitate its early detection.

[Development of novel therapeutic agents for myelofibrosis].

Myelofibrosis (MF) is a chronic myeloproliferative tumor with a poor prognosis that not only impairs the quality of life because of splenomegaly and debilitating systemic symptoms but also has a high acute myeloid leukemia progression rate. Ruxolitinib, a JAK inhibitor, enhances systemic symptoms in MF and prolongs survival; however, it is not effective in suppressing bone marrow fibrosis and leukemia progression, and allogeneic hematopoietic stem cell transplantation remains needed for treatment. As a result, many new drugs for MF are presently being developed. Many similar drugs have been demonstrated to enhance therapeutic effectiveness if combined with ruxolitinib, particularly BCL-2/BCL-XL inhibitors, bromodomain and extra-terminal domain inhibitors, and human double-minute homolog 2 inhibitors, to improve bone marrow fibrosis. This study provides an overview of drugs currently employed in clinical trials being performed in Japan.

Emerging immunotherapeutic strategies for the treatment of breast cancer.

Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.

Plant-based milk: unravel the changes of the antioxidant index during processing and storage - a review.

As a nutrient rich emulsion extracted from plant materials, plant-based milk (PBM) has been the latest trend and hot topic in the food industry due to the growing awareness of consumers toward plant-based products in managing the environmental (carbon footprint and land utility), ethical (animal well-fare) and societal (health-conscious) issues. There have been extensive studies and reviews done to discuss the distinct perspective of PBM including its production, health effects and market acceptance. However, not much has been emphasized on the valuable antioxidants present in PBM which is one of the attributes making them stand apart from dairy milk. The amounts of antioxidants in PBM are important. They offered tremendous health benefits in maintaining optimum health and reducing the risk of various health disorders. Therefore, enhancing the extraction of antioxidants and preserving their activity during production and storage is important. However, there is a lack of a comprehensive review of how these antioxidants changes in response to different processing steps involved in PBM production. Presumably, antioxidants in PBM could be potentially lost due to thermal degradation, oxidation or leaching into processing water. Hence, this paper aims to fill the gaps by addressing an extensive review of how different production steps (germination, roasting, soaking, blanching, grinding and filtration, and microbial inactivation) affect the antioxidant content in PBM. In addition, the effect of different microbial inactivation treatments (thermal or non-thermal processing) on the alteration of antioxidant in PBM was also highlighted. This paper can provide useful insight for the industry that aims in selecting suitable processing steps to produce PBM products that carry with them a health declaration.

Modulating the Activity of Androgen Receptor for Treating Breast Cancer.

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics.

The epidemic of diabetes mellitus (DM) necessitates the development of novel therapeutic and preventative strategies to attenuate complications of this debilitating disease. Diabetic cardiomyopathy (DCM) is a frequent disorder affecting individuals diagnosed with DM characterized by left ventricular hypertrophy, diastolic and systolic dysfunction and myocardial fibrosis in the absence of other heart diseases. Progression of DCM is associated with impaired cardiac insulin metabolic signaling, increased oxidative stress, impaired mitochondrial and cardiomyocyte calcium metabolism, and inflammation. Various non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), as well as their target genes are implicated in the complex pathophysiology of DCM. It has been demonstrated that miRNAs and lncRNAs play an important role in maintaining homeostasis through regulation of multiple genes, thus they attract substantial scientific interest as biomarkers for diagnosis, prognosis and as a potential therapeutic strategy in DM complications. This article will review the different miRNAs and lncRNA studied in the context of DM, including type 1 and type 2 diabetes and the contribution of pathophysiological mechanisms including inflammatory response, oxidative stress, apoptosis, hypertrophy and fibrosis to the development of DCM .

Noncoding RNAs in Papillary Thyroid Cancer: Interaction with Cancer-Associated Fibroblasts (CAFs) in the Tumor Microenvironment (TME) and Regulators of Differentiation and Lymph Node Metastasis.

A large majority of all thyroid cancers are papillary thyroid carcinomas (PTC), named for the specific papillary architecture observed histologically. Despite the high rate of success with modern diagnostic and therapeutic algorithms, there are significant areas where the management of PTC can be improved. Aggressive PTC subtypes that are refractory to radioactive iodine (RAI) therapy carry a more severe prognosis and account for most of PTC-related deaths. As lymph node metastasis is present in roughly 40% of all adult PTC cases, higher specificity in these tests is a clinical need, especially since lymph node metastases are associated with reduced survival and higher recurrence rates. Additionally, this cancer can progress to more dedifferentiated and aggressive variants, such as poorly differentiated papillary thyroid cancer (PDPTC) and anaplastic thyroid cancer (ATC). Therefore, development of more sensitive and specific detection methods that allow unnecessary surgeries to be avoided is of the utmost importance. The body of large-scale, unbiased gene expression analysis in PTC has focused on the coding transcriptome, specifically mRNAs and microRNAs. However, there have been implications for the potential use of long noncoding RNAs (lncRNAs) in PTC diagnosis, prognosis, and treatment via the utilization of genome-wide studies of patient samples. lncRNAs have diverse regulatory potential in gene expression, alternative splicing, posttranscriptional mRNA modification, and epigenomic alterations. Many lncRNAs have tissue-specific expression and are demonstrated to play key roles in cancer progression and prognosis. However, lncRNAs are not being exploited as biomarkers or therapeutic targets currently, despite their elucidated effects on oncogenesis. These potent biomarkers would be revolutionary in detection at early stages, as this significantly increases the chances of survival. Their aberrant expression in cancer and correlation with steps in tumorigenesis as well as their role in differentiation would allow for a promising role as a prognostic and diagnostic biomarker in thyroid cancer. This would help prevent the more aggressive ATC that derives from dedifferentiation of the less aggressive PTC and FTC. The targeting of the specific lncRNAs could also pose a valuable treatment option via preventing or reversing this dedifferentiation process and making this usually refractory form of thyroid cancer more responsive to standard treatment options.

[Development of future treatment for ATL].

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I. The clinical course of ATL is heterogeneous, and this condition has different types, which are as follows: acute, lymphoma, chronic, and smoldering. The chronic type is further subclassified into favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL and favorable chronic and smoldering-type ATL are defined as aggressive and indolent ATL, respectively. Newly identified prognostic indices based on clinical parameters and/or genetic predictors should be incorporated in the stratified treatment approach. The standard of care for aggressive ATL is multiagent chemotherapy, followed by allogeneic hematopoietic stem cell transplantation if applicable. Meanwhile, that for indolent ATL is watchful waiting until progression to the aggressive type. The combination of interferon-α and zidovudine is a treatment option for indolent ATL in other countries, and a confirmatory phase 3 trial is ongoing in Japan. In addition to mogamulizumab, lenalidomide, and brentuximab vedotin, which have been recently utilized in clinical practice, the use of a novel histone deacetylase (HDAC) inhibitor has been filed for approval. Moreover, an EZH1/2 inhibitor has completed the enrollment of a phase 2 trial in Japan. The standard of care for elderly patients should be established because the median age of those with newly diagnosed ATL reaches up to 70 years old.

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases.

Many cytokines are crucial drivers of cancers and autoimmune conditions. These proteins bind to receptors and signal their responses through Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Genetic variations in the JAK-STAT pathway are correlated with the increased risk of cancers, autoimmunity as well as inflammatory diseases. Targeting JAKs and STATs can be a safe and efficacious strategy for treating these diseases. Tofacitinib, as the first JAK inhibitor, is approved for rheumatoid arthritis therapy. Also, many other JAK inhibitors have been proven or are in various phases of clinical trials for various diseases. At present, small-molecule JAK inhibitors are considered as a novel category of drugs in the treatment of cancer and immune-mediated diseases.

Novel Treatment for Mitigating Condensate Bank Using a Newly Synthesized Gemini Surfactant.

Condensate accumulation in the vicinity of the gas well is known to curtail hydrocarbon production by up to 80%. Numerous approaches are being employed to mitigate condensate damage and improve gas productivity. Chemical treatment, gas recycling, and hydraulic fracturing are the most effective techniques for combatting the condensate bank. However, the gas injection technique showed temporary condensate recovery and limited improvement in gas productivity. Hydraulic fracturing is considered to be an expensive approach for treating condensate banking problems. In this study, a newly synthesized gemini surfactant (GS) was developed to prevent the formation of condensate blockage in the gas condensate reservoirs. Flushing the near-wellbore area with GS will change the rock wettability and thereby reduce the capillary forces holding the condensate due to the strong adsorption capacity of GS on the rock surface. In this study, several measurements were conducted to assess the performance of GS in mitigating the condensate bank including coreflood, relative permeability, phase behavior, and nuclear magnetic resonance (NMR) measurements. The results show that GS can reduce the capillary pressure by as much as 40%, increase the condensate mobility by more than 80%, and thereby mitigate the condensate bank by up to 84%. Phase behavior measurements indicate that adding GS to the oil-brine system could not induce any emulsions at different salinity levels. Moreover, NMR and permeability measurements reveal that the gemini surfactant has no effect on the pore system and no changes were observed in the T2 relaxation profiles with and without the GS injection. Ultimately, this work introduces a novel and effective treatment for mitigating the condensate bank. The new treatment showed an attractive performance in reducing liquid saturation and increasing the condensate relative permeability.

Baricitinib for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common inflammatory disease with several implications on health, disability and economy. Conventional treatment for RA centers on anti-inflammatory drugs and specific targeting of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Baricitinib is a novel, Food and Drug Administration (FDA) approved, once daily oral drug that is effective in combination with current treatment and results in significantly reduced symptoms with good safety profile. Further studies are required to find rare side effects and evaluate the long term efficacy in disease modulation and patient symptom reduction. This is a comprehensive review of the literature on baricitinib for the treatment of RA. This review provides an update on the pathophysiology, diagnosis and conventional treatment of RA, then proceeds to introduce baricitinib and the data that exists to support or refute its use in RA. The presented study also indicated clinical trials confirming the effectiveness of baricitinib in this indication.

Lower body negative pressure to safely reduce intracranial pressure.

KEY POINTS: During long-term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure 'unloading' associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non-linear dose-response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non-invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension. ABSTRACT: Patients with elevated intracranial pressure (ICP) exhibit neuro-ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space-flight where lack of gravitational stress prevents daily lowering of ICP associated with upright posture. Lower body negative pressure (LBNP) simulates the effects of gravity by displacing fluid caudally and we hypothesized that LBNP would lower ICP without compromising cerebral perfusion. Ten cerebrally intact volunteers were included: six ambulatory neurosurgical patients with parenchymal ICP-sensors and four former cancer patients with Ommaya-reservoirs to the frontal horn of a lateral ventricle. We applied LBNP while recording ICP and blood pressure while supine, and during simulated intracranial hypertension by 15° head-down tilt. LBNP from 0 to 50 mmHg at increments of 10 mmHg lowered ICP in a non-linear dose-dependent fashion; when supine (n = 10), ICP was decreased from 15 ± 2 mmHg to 14 ± 4, 12 ± 5, 11 ± 4, 10 ± 3 and 9 ± 4 mmHg, respectively (P < 0.0001). Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure at midbrain level minus ICP, was unchanged (from 70 ± 12 mmHg to 67 ± 9, 69 ± 10, 70 ± 12, 72 ± 13 and 74 ± 15 mmHg; P = 0.02). A 15° head-down tilt (n = 6) increased ICP to 26 ± 4 mmHg, while application of LBNP lowered ICP (to 21 ± 4, 20 ± 4, 18 ± 4, 17 ± 4 and 17 ± 4 mmHg; P < 0.0001) and increased CPP (P < 0.01). An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight-associated neuro-ocular syndrome in astronauts. Furthermore, LBNP holds clinical potential as a safe, non-invasive method for lowering ICP and improving CPP for patients with pathologically elevated ICP on Earth.

Novel treatment options in the management of metastatic castration-naïve prostate cancer; which treatment modality to choose?

Androgen-deprivation therapy (ADT) has been the mainstay of treatment of metastatic prostate cancer since the first report of its hormonal dependence in the 1940s. Since 2015, the addition of docetaxel and the addition of abiraterone to ADT have conferred substantial overall survival benefit in men with metastatic castration-naïve prostate cancer (mCNPC). The shift of these treatment options for metastatic prostate cancer from the castration-resistant setting to the castration-naïve setting has led to new challenges in the management of this disease. It remains to be determined which patients may benefit most from either early concomitant docetaxel or from abiraterone with ADT, since biomarkers for early therapy response and risk stratification are currently lacking. Therefore, the ability to personalize medicine is hampered. Furthermore, the earlier detection of metastatic prostate cancer by using new imaging modalities makes the application of clinical trial results in daily practice increasingly challenging. Recently, both local radiotherapy to the primary tumor combined with ADT and abiraterone combined with ADT showed a survival benefit in low-volume disease patients. The latest data also demonstrated a survival benefit with the addition of apalutamide or enzalutamide to ADT. The extent of metastatic disease may become one of the most important factors to determine treatment choice. In this review article, we summarize trial data to provide guidance for treatment selection in metastatic castration-naïve prostate cancer.

An update on emerging drugs for the treatment of erectile dysfunction.

Introduction: Erectile dysfunction is an extremely frequent and extensively studied condition, currently affecting the lives of tens of millions of men around the globe. The extensive knowledge of its pathophysiology has led to the development of phosphodiesterase 5-inhibitors, which can facilitate sexual intercourse in a large number of patients. However, an ever-increasing number of patients is unresponsive to these drugs due to underlying comorbidities or previous surgery. Different molecular pathways need to be addressed to provide treatment for a larger patient population. Areas covered: In this paper, we will review the underlying molecular pathways, discuss already available treatment options and their limitations and provide an overview of the newest therapeutics in development. Centrally and peripherally acting agents will be discussed separately. Additionally, newest advances in regenerative medicine options will be discussed. Expert opinion: Even though novel drugs have not been tested in a phase III setting, several phase II clinical trial results are eagerly awaited. These newest therapeutics could be applied as monotherapy or combination therapy in the subset of patients unresponsive to traditional treatment options.

Long-Acting Growth Hormone Preparations in the Treatment of Children.

Human growth hormone (hGH), which had been in use since 1958, was supplanted by recombinant human growth hormone (rhGH) in 1985 for those with growth hormone deficiency (GHD). Adherence to daily subcutaneous growth hormone is challenging for patients. Thus, several companies have pursued the creation of long acting rhGH. These agents can be divided broadly into depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding GH and GH fusion proteins. Nutropin Depot is the only long acting rhGH ever approved by the U.S. Food and Drug Administration, and it was removed from the market in 2004. Of the approximately seventeen candidate drugs, only a handful remain under active clinical investigation or are commercially available.

Reproducibility of patient setup in the seated treatment position: A novel treatment chair design.

Radiotherapy in a seated position may be indicated for patients who are unable to lie on the treatment couch for the duration of treatment, in scenarios where a seated treatment position provides superior anatomical positioning and dose distributions, or for a low-cost system designed using a fixed treatment beam and rotating seated patient. In this study, we report a novel treatment chair that was constructed to allow for three-dimensional imaging and treatment delivery while ensuring robust immobilization, providing reproducibility equivalent to that in the traditional supine position. Five patients undergoing radiation treatment for head-and-neck cancers were enrolled and were setup in the chair, with immobilization devices created, and then imaged with orthogonal X-rays in a scenario that mimicked radiation treatments (without treatment delivery). Six subregions of the acquired images were rigidly registered to evaluate intra- and interfraction displacement and chair construction. Displacements under conditions of simulated image guidance were acquired by first registering one subregion; the residual displacement of other subregions was then measured. Additionally, we administered a patient questionnaire to gain patient feedback and assess comparison to the supine position. Average inter- and intrafraction displacements of all subregions in the seated position were less than 2 and 3 mm, respectively. When image guidance was simulated, L-R and A-P interfraction displacements were reduced by an average of 1 mm, providing setup of comparable quality to supine setups. The enrolled patients, who had no indication for a seated treatment position, reported no preference in the seated or the supine position. The novel chair design provides acceptable inter- and intrafraction displacement, with reproducibility equivalent to that reported for patients in the supine position. Patient feedback will be incorporated in the refinement of the chair, facilitating treatment of head-and-neck cancer in patients who are unable to lie for the duration of treatment or for use in an economical fixed-beam setup.

New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis.

Schizophrenia has been primarily associated with dopamine dysfunction, and treatments have been developed that target the dopamine pathway in the central nervous system. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid (GABA) signaling, which may lead to aberrant functioning of interneurons that manifest as cognitive, behavioral, and social dysfunction through altered functioning of a broad range of macro- and microcircuits. The interactions between neurotransmitters can be modeled as nodes and edges by using graph theory, and oxidative balance, immune, and glutamatergic systems may represent multiple nodes interlocking at a central hub; imbalance within any of these nodes might affect the entire system. Therefore, this review attempts to address novel treatment targets beyond the dopamine hypothesis, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines. Furthermore, we outline that these treatment targets can be possibly integrated with novel treatment strategies aimed at different symptoms or phases of the illness. We anticipate that reversing anomalous activity in these novel treatment targets or combinations between these strategies might be beneficial in the treatment of schizophrenia.