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Targeted therapy - Top 30 Publications

Severe Lower Extremity Infections Treated with Hip Disarticulation - Case Series.

Hip disarticulation is a major ablative procedure with serious risks as well as consequences for the patient, performed rarely for a lower extremity infection. According to literature, the mortality rate in these procedures reaches up to 60%. Unfavourable prognostic factors are emergency surgeries without adequate preparation of the patient and surgeries indicated for an ischemic terrain infection. The authors present four cases of hip disarticulation for severe lower extremity infection. In one patient, the procedure was performed urgently for necrotising fasciitis in the lower extremity extending up to the groin area, in the other three patients for non-healing femoral stump infection following the lower extremity amputation for vascular causes, of which two cases got complicated by the presence of TKA. Two of the patients treated surgically for stump infection died two months after the surgery due to respiratory complications. The two surviving patients underwent the last check one year following the surgery, they are both capable of independent locomotion with two underarm crutches and use the prosthesis only rarely. In the discussion, the factors influencing the mortality rate of the procedure, the principles of surgical and antimicrobial therapy, and the use of the negative-pressure wound therapy are analysed. The underlying principles of the care for patients with severe infections of the musculoskeletal system are infection focus debridement with the removal of foreign material, antibiotic (anti-infective) therapy targeted based on the cultivation results, wound management aimed to prevent contamination with nosocomial strains, and multidisciplinary cooperation - orthopaedist/surgeon, infectious disease physician, intensive care specialist, nutrition and rehabilitation specialist, nursing and prosthetic care providers. Key words: hip disarticulation, infection, necrotizing fasciitis.

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.

The Role of Cadaverine Synthesis on Pneumococcal Capsule and Protein Expression.

Invasive infections caused by Streptococcus pneumoniae, a commensal in the nasopharynx, pose significant risk to human health. Limited serotype coverage by the available polysaccharide-based conjugate vaccines coupled with increasing incidence of antibiotic resistance complicates therapeutic strategies. Bacterial physiology and metabolism that allows pathogens to adapt to the host are a promising avenue for the discovery of novel therapeutics. Intracellular polyamine concentrations are tightly regulated by biosynthesis, transport and degradation. We previously reported that deletion of cadA, a gene that encodes for lysine decarboxylase, an enzyme that catalyzes cadaverine synthesis results in an attenuated phenotype. Here, we report the impact of cadA deletion on pneumococcal capsule and protein expression. Our data show that genes for polyamine biosynthesis and transport are downregulated in ∆cadA. Immunoblot assays show reduced capsule in ∆cadA. Reduced capsule synthesis could be due to reduced transcription and availability of precursors for synthesis. The capsule is the predominant virulence factor in pneumococci and is critical for evading opsonophagocytosis and its loss in ∆cadA could explain the reported attenuation in vivo. Results from this study show that capsule synthesis in pneumococci is regulated by polyamine metabolism, which can be targeted for developing novel therapies.

Overexpression of the Neuronal Human (Pro)renin Receptor Mediates Angiotensin II-Independent Blood Pressure Regulation in the Central Nervous System.

Despite advances in anti-hypertensive therapeutics, at least 15-20% of hypertensive patients have resistant hypertension through mechanisms that remain poorly understood. In this study, we provide a new mechanism for regulation of blood pressure (BP) in the central nervous system (CNS) by the (pro)renin receptor (PRR), a recently identified component of the renin-angiotensin system (RAS) that mediates angiotensin II (Ang II) formation in the CNS. Although the PRR also mediates Ang II-independent signaling, the importance of these pathways in BP regulation is unknown. Here, we developed a unique transgenic mouse model overexpressing the human PRR (hPRR) specifically in neurons (Syn-hPRR). Intracerebroventricular (ICV) infusion of human prorenin caused neurogenic hypertension in Syn-hPRR mice. This hypertensive response was attenuated by an NADPH oxidase (NOX) inhibitor, but not by anti-hypertensive agents that target the RAS. Using a brain-targeted genetic-knockdown approach, we found that NOX4 was the key isoform responsible for prorenin-induced elevation of BP in Syn-hPRR mice. Moreover, inhibition of extracellular signal-regulated kinase (ERK) significantly attenuated the increase in NOX activity and BP induced by human prorenin. Collectively, our findings indicate that an Ang II-independent, PRR-mediated signaling pathway regulates BP in the CNS by a PRR-ERK-NOX4 mechanism.

Nanoplatform Assembled from a CD44-Targeted Prodrug and Smart Liposomes for Dual Targeting of Tumor Microenvironment and Cancer Cells.

The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, invasion and metastasis. Therefore, a therapy that combines chemotherapeutic drugs with a TME modulator could be a promising route for cancer treatment. This paper reports a nanoplatform self-assembled from a hyaluronic acid (HA)-paclitaxel (PTX) (HA-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the TME and cancer cells. Interestingly, the prodrug HA-PTX can self-assemble on both positively and negatively charged liposomes, forming hybrid nanoparticles (HNPs, 100 nm). Triggered by mild hyperthermia, HA-PTX/MATT-LTSLs HNPs rapidly release their payloads into the extracellular environment, and the released HA-PTX quickly enters 4T1 cells through a CD44-HA affinity. The HNPs possess promoted tumor accumulation (1.6-fold), exhibit deep tumor penetration, and significantly inhibit the tumor growth (10-fold), the metastasis (100%) and angiogenesis (10-fold), etc. Importantly, by targeting the TME and maintaining its integrity via inhibiting the expression and activity of matrix metalloproteinases (MMPs) (> 5-fold), blocking the fibroblast activation through downregulating the TGF-β1 expression (5-fold) and suppressing the degradation of extracellular matrix, the HNPs allow for significant metastasis inhibition. Overall, these findings indicate that a prodrug of an HA-hydrophobic-active compound and liposomes can be self-assembled into a smart nanoplatform for the dual targeting of the TME and tumor cells and efficient combined treatment; additionally, the co-delivery of MATT and HA-PTX with the HNPs is a promising approach for the treatment of metastatic cancer. This study creates opportunities for fabricating multifunctional nanodevices and offers an efficient strategy for disease therapy.

Enhancement of antitumor activity by using 5-ALA-mediated sonodynamic therapy to induce apoptosis in malignant gliomas: significance of high-intensity focused ultrasound on 5-ALA-SDT in a mouse glioma model.

OBJECTIVE High invasiveness of malignant gliomas frequently causes early local recurrence of the tumor, resulting in extremely poor outcome. To control such recurrence, novel therapies targeted toward infiltrating glioma cells around the tumor border are required. Here, the authors investigated the antitumor activity of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas to explore the possibility for clinical use of 5-ALA-mediated SDT (5-ALA-SDT). METHODS In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry and TUNEL staining. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined by analysis of the effect of pretreatment with the radical scavenger edaravone. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated. RESULTS The 5-ALA-SDT inhibited cell growth and changed cell morphology, inducing cell shrinkage, vacuolization, and swelling. Flow cytometric analysis and TUNEL staining indicated that 5-ALA-SDT induced apoptotic cell death in all gliomas. The 5-ALA-SDT generated significantly higher ROS than in the control group, and inhibition of ROS generation by edaravone completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. The proliferative activity of the entire tumor was markedly decreased. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact. CONCLUSIONS The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field, whereas the surrounding brain tissue remained normal, resulting in longer survival of the HIFU-treated mice compared with that of untreated mice. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

ABP 980: Promising Trastuzumab Biosimilar for HER2-Positive Breast Cancer.

Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for "ABP 980" or "trastuzumab biosimilar". "ABP 980 and breast cancer" or "trastuzumab biosimilar and breast cancer" were used to search for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

Specific expression of PD-L1 in RELA-fusion supratentorial ependymoma: Implications for PD-1-targeted therapy.

A desperate need for novel therapies in pediatric ependymoma (EPN) exists, as chemotherapy remains ineffective and radiotherapy often fails. EPN have significant infiltration of immune cells, which correlates with outcome. Immune checkpoint inhibitors provide an avenue for new treatments. This study characterizes tumor-infiltrating immune cells in EPN and aims at predicting candidates for clinical trials using checkpoint inhibitors targeting PD-L1/PD-1 (programmed death ligand 1/programmed death 1).

Alveolar soft part sarcoma in children and young adults: A report of 69 cases.

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by ASPL-TFE3 translocation. Apart from complete surgical resection, there is no standard management strategy.

Antitumor effects of radionuclide treatment using α-emitting meta-211At-astato-benzylguanidine in a PC12 pheochromocytoma model.

Therapeutic options for patients with malignant pheochromocytoma are currently limited, and therefore new treatment approaches are being sought. Targeted radionuclide therapy provides tumor-specific systemic treatments. The β-emitting radiopharmaceutical meta-131I-iodo-benzylguanidine (131I-MIBG) provides limited survival benefits and has adverse effects. A new generation of radionuclides for therapy using α-particles including meta-211At-astato-benzylguanidine (211At-MABG) are expected to have strong therapeutic effects with minimal side effects. However, this possibility has not been evaluated in an animal model of pheochromocytoma. We aimed to evaluate the therapeutic effects of the α-emitter 211At-MABG in a pheochromocytoma model.

Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer's disease.

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer's disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates - such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.


Radiation therapy (from external beams to unsealed and sealed radionuclide sources) takes advantage of the detrimental effects of the clustered production of radicals and reactive oxygen species (ROS). Research has mainly focused on the interaction of radiation with water, which is the major constituent of living beings, and with nuclear DNA, which contains the genetic information. This led to the so-called "target" theory according to which cells have to be hit by ionizing particles to elicit an important biological response, including cell death. In cancer therapy, the Poisson law and linear quadratic mathematical models have been used to describe the probability of hits per cell as a function of the radiation dose. However, in the last twenty years, many studies have shown that radiation generates "danger" signals that propagate from irradiated to non-irradiated cells, leading to bystander and other off-target effects. Like for targeted effects, redox mechanisms play a key role also in off-target effects through transmission of ROS and reactive nitrogen species (RNS), but also of cytokines, ATP and extracellular DNA. Particularly, nuclear factor kappa B is essential for triggering self-sustained production of ROS and RNS, thus making the bystander response similar to inflammation. In some therapeutic situations, this phenomenon is associated with recruitment of immune cells that are involved in distant irradiation effects (called "away-from-target" i.e. abscopal effects). Determining the contribution of targeted and off-target effects in the clinic is still challenging. This has important consequences in radiotherapy, but also possibly in diagnostic procedures and in radiation protection.

Adjuvant Endocrine Therapy.

The use of hormonal therapy in breast cancer has improved the overall outcome for patients with early-stage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy. Ongoing studies are evaluating the role of additional targeted therapies, such as CDK4/6 inhibitors, to further improve outcome for patients with early-stage hormone receptor-positive breast cancer.

Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice.

Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg). Intraductal delivery of 1 × 1011 vg scAAV6.GFP transduced acini, ductal cells, and islet cells with >50%, ∼48%, and >80% efficiency, respectively, and >80% pancreatic transduction was achieved with 5 × 1011 vg. In a KrasG12D-driven pancreatic cancer mouse model, intraductal delivery of scAAV6.GFP targeted acini, epithelial, and stromal cells and exhibited persistent gene expression 5 months post-delivery. In normal mice, intraductal delivery induced a transient increase in serum amylase/lipase that resolved within a day of infusion with no sustained pancreatic inflammation or fibrosis. Similarly, in PDAC mice, intraductal delivery did not increase pancreatic intraepithelial neoplasia progression/fibrosis. Our study demonstrates that scAAV6 targets the pancreas/neoplasm efficiently and safely via retrograde pancreatic intraductal delivery.

Unusual cause of severe diabetic ketoacidosis precipitated by Streptococcus bovis/equinus (SBSEC) bacteremia: Case report and review of literature.

Diabetic ketoacidosis is a feared complication in patients with diabetes mellitus and poses high risk of mortality and morbidity unless treated in timely manner. Infection is one of the most common precipitating factors for the development of diabetic ketoacidosis. Bacteremia with Group A and Group B beta hemolytic streptococcal strains are well known, however nonenterococcal Group D strains such as the Streptococcus bovis/Streptococcus equinus complex (SBSEC) still remains an understudied entity. Here we present a case of a 35-year-old Type I diabetic female presenting with severe diabetic ketoacidosis with overlapping features of hyperosmolar hyperglycemia, precipitated by Streptococcus alactolyticus bacteremia, successfully treated with four-week course of parenteral ceftriaxone. This case report emphasizes the potential importance of SBSEC as an emerging pathologic strain and culprit for triggering diabetic ketoacidosis which requires prompt diagnosis and targeted therapy.

Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells.

Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin's lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen. Because PTCLs develop from mature T-cells, these NHLs are commonly CD4+, and CD4 is highly and uniformly expressed. Therefore, CD4 is an ideal target for PTCL CAR immunotherapy. To that effect, we created a robust third-generation anti-CD4 CAR construct (CD4CAR) and introduced it into clonal NK cells (NK-92). CD4CAR NK-92 cells specifically and robustly eliminated diverse CD4+ human T-cell leukemia and lymphoma cell lines (KARPAS-299, CCRF-CEM, and HL60) and patient samples ex vivo. Furthermore, CD4CAR NK-92 cells effectively targeted KARPAS-299 cells in vivo that modeled difficult-to-access lymphoma nodules, significantly prolonging survival. In our study, we present novel targeting of CD4 using CAR-modified NK cells, and demonstrate efficacy. Combined, our data support CD4CAR NK cell immunotherapy as a potential new avenue for the treatment of PTCLs and CD4+ T-cell malignancies.

Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency.

Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies. Proteomic analysis of more than 600 glioblastoma-specific proteins revealed, for the first time, that expression of acid ceramidase (ASAH1) is associated with poor glioblastoma survival. CD133+ GSCs express significantly higher ASAH1 compared to CD133- GSCs and serum-cultured glioblastoma cell lines, such as U87MG. These findings implicate ASAH1 as a plausible independent prognostic marker, providing a target for a therapy tailored toward GSCs. We further demonstrate that ASAH1 inhibition increases cellular ceramide level and induces apoptosis. Strikingly, U87MG cells, and three different patient-derived glioblastoma stem-like cancer cell lines were efficiently killed, through apoptosis, by three different known ASAH1 inhibitors with IC50's ranging from 11-104 μM. In comparison, the standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials.

A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy.

Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, π-π stacking, cation-π contacts and hydrophobic interactions with the surrounding amino acids in the active site. PU-H71-TPP selectively accumulated in mitochondria of tumor cells (17-fold increase in mitochondria/cytosol ratio), whereas unmodified PU-H71 showed minimal mitochondrial localization. Treatment of tumor cells with PU-H71-TPP dissipated mitochondrial membrane potential, inhibited oxidative phosphorylation in sensitive cell types, and reduced ATP production, resulting in apoptosis and tumor cell killing. Unmodified PU-H71 had no effect. Bioinformatics analysis identified a "mitochondrial Hsp90" signature in Acute Myeloid Leukemia (AML), which correlates with worse disease outcome. Accordingly, inhibition of mitochondrial Hsp90s killed primary and cultured AML cells, with minimal effects on normal peripheral blood mononuclear cells. These data demonstrate that directing Hsp90 inhibitors with different chemical scaffolds to mitochondria is feasible and confers improved anticancer activity. A potential "addiction" to mitochondrial Hsp90s may provide a new therapeutic target in AML.

Design and Synthesis of Isoquinolidinobenzodiazepine Dimers, a Novel Class of Antibody-Drug Conjugate Payload.

Antibody-drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D211), a new class of PBD dimer family of DNA damaging payloads. We have successfully synthesized all three IQB stereoisomers, experimentally showed that the purified (S,S)-D211 isomer is functionally more active than (R,R)-D221 and (S,R)-D231 isomers by >50,000-fold and ∼200-fold, respectively. We also synthesized a linker-payload (D212) that uses (S,S)-D211 payload with a cathepsin cleavable linker, a hydrophilic PEG8 spacer, and a thiol reactive maleimide. In addition, homogeneous ADCs generated using D212 linker-payload exhibited ideal physicochemical properties, and anti-CD33 ADC displayed a robust target-specific potency on AML cell lines. These results demonstrate that D212 linker-payload described here can be utilized for developing novel ADC therapeutics for targeted cancer therapy.

Current and Emerging Therapy on Lupus Nephritis.

Lupus nephritis (LN) is involvement of the kidney in patient with systemic lupus erythematosus (SLE) and one of the most common target organ in SLE. The diagnosis of LN will significantly impact the clinical outcome and therapy of the patient. Therapy regiment of LN is divided into two stages, induction and maintenance treatment. The main objective of the induction therapy is to achieve complete or partial remission as soon as possible since it is correlated with better prognosis and fewer relapse incidence. In the maintenance stage, the main aim of the therapy is to maintain the remission status and avoid future relapse. It is also important to evaluate the effectiveness of the therapy as it will affect the duration and the regiment therapy being used. Corticosteroid, cyclophosphamide, mycophenolate mofetil, azathrioprine, cyclosporine and tacrolimus are example of drugs used in LN therapy. Currently, studies are being conducted to evaluate and develop targeted drug therapy to further add treatment options for LN.

Cancer Stem Cells and Molecular Biology Test in Colorectal Cancer: Therapeutic Implications.

Colorectal cancer (CRC) is the third most frequent cancer in males, the second in females, and is the second leading cause of cancer related death worldwide. Within Indonesia's 250 million population, the incidence rates for CRC per 100,000 population were 15.2 for males and 10.2 for females, and estimated 63,500 cases per year.  More than 50% of colorectal cancer patients will develop metastasis. CRC is still the main cause of tumor-related death, and although most CRC patients are treated with surgery to remove the tumor tissue, some of the CRC patients recurred. Chemotherapy used as adjuvant or neoadjuvant therapy also has several problems, in which these treatments are useless in tumor cells with chemo-resistance. Molecular testing of CRC from tumor tissues has important implications for the selection of treatment. Biomarkers can be used as prognostic value, molecular predictive factors, and targeted therapy. Recent research reported that, cancer stem cells (CSCs) are considered as the origin of tumorigenesis, development, metastasis and recurrence. At present, it has been shown that CSCs existed in many tumors including CRC. This review aims to summarize the issue on CSCs, and the future development of drugs that target colorectal cancer stem cells.

Non-mammalian models of multiple endocrine neoplasia type 2.

Twenty-five years ago, RET was identified as the primary driver of multiple endocrine neoplasia type 2 (MEN2) syndrome. MEN2 is characterized by several transformation events including pheochromocytoma, parathyroid adenoma and, especially penetrant, medullary thyroid carcinoma (MTC). Overall, MTC is a rare but aggressive type of thyroid cancer for which no effective treatment currently exists. Surgery, radiation, radioisotope treatment and chemotherapeutics have all shown limited success, and none of these approaches have proven durable in advanced disease. Non-mammalian models that incorporate the oncogenic RET isoforms associated with MEN2 and other RET-associated diseases have been useful in delineating mechanisms underlying disease progression. These models have also identified novel targeted therapies as single agents and as combinations. These studies highlight the importance of modeling disease in the context of the whole animal, accounting for the complex interplay between tumor and normal cells in controlling disease progression as well as response to therapy. With convenient access to whole genome sequencing data from expanded thyroid cancer patient cohorts, non-mammalian models will become more complex, sophisticated and continue to complement future mammalian studies. In this review, we explore the contributions of non-mammalian models to our understanding of thyroid cancer including MTC, with a focus on Danio rerio and Drosophila melanogaster (fish and fly) models.

Novel targeted therapeutics for MEN2.

The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

Blood lactate is a predictor of short-term mortality in patients with myocardial infarction complicated by heart failure but without cardiogenic shock.

Mortality in patients with acute myocardial infarction (AMI) has improved substantially with modern therapy including percutaneous coronary interventions (PCI) but remains high in certain subgroups such as patients presenting with overt cardiogenic shock. However, the risk for AMI in patients presenting acutely with signs of heart failure but without cardiogenic shock is less well described. We aimed to identify risk factors for mortality in AMI patients with heart failure without overt cardiogenic shock.

Changing character: A narrative review of personality change in psychotherapies for personality disorder.

Personality disorder (PD) is a negative prognostic indicator for treatment, and absolute improvements in functioning among these patients are often modest. This may be because personality features that give rise to dysfunction in PD are not targeted optimally during most treatments.

Modulation of MicroRNAs 34a and 21 Affects Viability, Senescence, and Invasion in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is an aggressive and invasive brain tumor. Current interventional strategies have been minimally successful. Three key characteristics of GBMs are (1) enhanced resistance to apoptosis, (2) increased proliferation rate, and (3) increased invasion potential, making them difficult to treat. MicroRNAs (miRs) have demonstrated beneficial therapeutic intervention; particularly miRs 34a and 21, which have been implicated in regulation of apoptosis, senescence, and invasion of GBM tumor cells. MiR21 is anti-apoptotic and pro-proliferative, whereas miR34a is proapoptotic and an anti-invasive regulator in tumor cells. Our study investigates the effects of modulating both miR34a and miR21, in addition to comparing the two individual treatments. Using targeted cationic liposomes that bind to the epidermal growth factor receptor (EGFR), we delivered miR34a and/or anti-sense oligonucleotide to miR21 (ASO21) to GBM tumor cell lines, U87MG and A172, in vitro. Our data demonstrate that co-delivery of miR34a and ASO21 results in enhanced reduction in viability and invasion, while increasing senescence in vitro. Additionally, there were significant decreases in pro-invasion and -proliferation gene markers, as well as an increase in pro-apoptotic markers. In vivo results demonstrate that the combination of miR34a and ASO21 reduced tumor volume and proliferation of the A172 tumor cells. Accumulation of rhodamine encapsulated EGFR-targeted cationic liposomes was observed throughout the primary tumor bed after systemic injection. To our knowledge, we are the first to modulate multiple miRs, while using a targeted cationic liposomal delivery for miR-based therapy. These results demonstrate a potential clinically relevant, miR therapeutic strategy for GBM.

Nanotheranostic Based Iron Oxide (Fe₃O₄) Saturated Lactoferrin Nanocapsules for Colonic Adenocarcinoma.

Efficient early detection of cancer and its simultaneous therapy can improve the survival of cancer patients significantly. Recently there is great interest for the development of nanotheranostic systems with multimodal live real-time imaging ability. Novel multimodal multifunctional iron oxide (Fe3O4) saturated lactoferrin (FebLf) nanocapsules/nanocarriers (FebLf NCs) nanoformulation was fabricated. Anti-cancer nanotheranostic ability in human xenograft colonic adenocarcinoma model was conducted in vivo by employing near infrared flouroscence (NIRF) real time live mice imaging technology. FebLf NCs showed spherical morphology with 50 to 80 nm size with super paramagnetic property and exhibited profound in vivo anti-tumour efficacy, leading to regression of the xenograft colonic tumour growth over a 90 day trial period. NIRF real time imaging revealed selective localisation patterns of the FebLf NCs at the tumour site causing tumour growth inhibition. In turn, ex vivo NIRF imaging of mice organs showed enhanced tumoural uptake and biodistribution at the vital organs including spleen, intestine, kidney, and intestine. Low-density lipoprotein receptors (LDLRs), ferroportin, ferritin receptor based in vivo internalisation mechanisms and iron metabolism regulation were observed. Histopathological analysis revealed obsolute non-toxic nature of FebLf NCs in mice tissues. These observations summate biocompatible, multimodal anticancer activity of novel FebLf NCs for real time cancer therapeutic imaging leading to targeted colonic adenocarcinoma therapy.

Linkages of nuclear architecture to biological and pathological control of gene expression.

Functional interrelationships between components of nuclear architecture and control of gene expression are becoming increasingly evident. There is growing appreciation that multiple levels of nuclear organization integrate the regulatory cues that support activation and suppression of genes as well as the processing of gene transcripts. The linear organization of genes and promoter elements provide the potential for responsiveness to physiological regulatory signals. Parameters of chromatin structure and nucleosome organization support synergism between activities at independent regulatory sequences and render promoter elements accessible or refractory to transcription factors. Association of genes, transcription factors, and the machinery for transcript processing with the nuclear matrix facilitates fidelity of gene expression within the three-dimensional context of nuclear architecture. Mechanisms must be defined that couple nuclear morphology with enzymatic parameters of gene expression. The recent characterization of factors that mediate chromatin remodeling and intranuclear targeting signals that direct transcription factors to subnuclear domains where gene expression occurs, reflect linkage of genetic and structural components of transcriptional control. Nuclear reorganization and aberrant intranuclear trafficking of transcription factors for developmental and tissue-specific control that occurs in tumor cells and in neurological disorders provides a basis for high resolution diagnostics and targeted therapy. J. Cell. Biochem. Suppls. 30/31:220-231, 1998. © 1998 Wiley-Liss, Inc.

BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.

BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy.

Xylose donor transport is critical for fungal virulence.

Cryptococcus neoformans, an AIDS-defining opportunistic pathogen, is the leading cause of fungal meningitis worldwide and is responsible for hundreds of thousands of deaths annually. Cryptococcal glycans are required for fungal survival in the host and for pathogenesis. Most glycans are made in the secretory pathway, although the activated precursors for their synthesis, nucleotide sugars, are made primarily in the cytosol. Nucleotide sugar transporters are membrane proteins that solve this topological problem, by exchanging nucleotide sugars for the corresponding nucleoside phosphates. The major virulence factor of C. neoformans is an anti-phagocytic polysaccharide capsule that is displayed on the cell surface; capsule polysaccharides are also shed from the cell and impede the host immune response. Xylose, a neutral monosaccharide that is absent from model yeast, is a significant capsule component. Here we show that Uxt1 and Uxt2 are both transporters specific for the xylose donor, UDP-xylose, although they exhibit distinct subcellular localization, expression patterns, and kinetic parameters. Both proteins also transport the galactofuranose donor, UDP-galactofuranose. We further show that Uxt1 and Uxt2 are required for xylose incorporation into capsule and protein; they are also necessary for C. neoformans to cause disease in mice, although surprisingly not for fungal viability in the context of infection. These findings provide a starting point for deciphering the substrate specificity of an important class of transporters, elucidate a synthetic pathway that may be productively targeted for therapy, and contribute to our understanding of fundamental glycobiology.