This document discusses limitations of anti-angiogenic therapy for treating cancer. It explains that tumors can develop resistance to anti-angiogenic drugs by activating alternative angiogenic pathways or recruiting pericytes to support new blood vessel growth. While initial studies showed promise, clinical trials found only modest increases in progression-free survival and no enduring responses. The document also notes that anti-angiogenic therapy may paradoxically cause tumors to become more invasive and metastatic in some cases. Combination therapies targeting multiple angiogenic factors or pericytes may be needed to overcome resistance.
Consensus or Controversy Should Mutational Analysis (Ma) Be Considered as a R...CrimsonpublishersCancer
Unique amongst most solid malignancies, gastrointestinal stromal tumors (GISTs) are addicted to a few specific oncogenic drivers and are uniformly resistant to cytotoxic chemotherapeutics but sensitive to tyrosine kinase inhibitors (TKIs). Similar to all cancers, GISTs are heterogenous and subclassified into distinct entities according molecular alterations. It is unquestionable that mutational status offers both prognostic as well as predictive value to guide clinical management of GISTs in both advanced/metastatic and curative/(neo)adjuvant settings. One would therefore assume that mutational analysis would be routine and adopted routinely in terms of timing in the clinical management of GIST, but in practice the assessment of mutational analysis is not adopted routinely. In this paper we will discuss the impact of mutational analysis on clinical management of GIST, as well as review currently guidelines for mutational analysis and review possible reasons for lack of uptake of routine testing in practice.
Dose selection trial of metronomic oral vinorelbine monotherapy in patients w...Enrique Moreno Gonzalez
Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer.
Consensus or Controversy Should Mutational Analysis (Ma) Be Considered as a R...CrimsonpublishersCancer
Unique amongst most solid malignancies, gastrointestinal stromal tumors (GISTs) are addicted to a few specific oncogenic drivers and are uniformly resistant to cytotoxic chemotherapeutics but sensitive to tyrosine kinase inhibitors (TKIs). Similar to all cancers, GISTs are heterogenous and subclassified into distinct entities according molecular alterations. It is unquestionable that mutational status offers both prognostic as well as predictive value to guide clinical management of GISTs in both advanced/metastatic and curative/(neo)adjuvant settings. One would therefore assume that mutational analysis would be routine and adopted routinely in terms of timing in the clinical management of GIST, but in practice the assessment of mutational analysis is not adopted routinely. In this paper we will discuss the impact of mutational analysis on clinical management of GIST, as well as review currently guidelines for mutational analysis and review possible reasons for lack of uptake of routine testing in practice.
Dose selection trial of metronomic oral vinorelbine monotherapy in patients w...Enrique Moreno Gonzalez
Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer.
The maturation of genomic technologies has enabled new
discoveries in disease pathogenesis as well as new approaches to patient care.
In pediatric oncology, patients may now receive individualized genomic analysis to identify molecular aberrations of relevance for diagnosis and/or treatment.
Several recent clinical studies have begun to explore the feasibility and utility of genomics-driven precision medicine.
THERAPEUTIC POTENTIAL OF ANGIOGENESIS INHIBITOR MIXTURES IN CANCER TREATMENT,...ANCA MARIA CIMPEAN
ABSTRACT
It is generally understood that improvement of cancer therapies is achieved by the combination of drugs. This approach will improve efficacy, while toxicity and the risk for drug resistance may be decreased. In this review, the efforts on combining drugs for the treatment of two tumor types is highlighted, followed by a description of the challenges that are faced in designing optimal combination therapies.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
ST-001 NanoFenretinide - SciTech Development Lead Drug CompoundSciTech Development
SciTech’s lead compound, ST-001, is a small-molecule immune oncology (IO) nanoFenretinide cancer drug employed as an aqueous nanoparticle suspension for IV administration. The ST-001 nanoFenretinide drug is comprised of the active pharmaceutical ingredient (API) fenretinide in a patented combination with carefully selected phospholipids (inactive ingredients). ST-001 is designed to deliver a 15-fold higher drug to lipid ratio and a >6x concentration of the API than conventional IV formulations achieving therapeutically effective doses without the toxic side effects observed with other delivery systems – a benefit previously unattainable. Recent discovery of the API’s immunotherapeutic effect, in which a reactivated natural immune response compliments the previously understood safe, direct, chemotherapeutic effect (functioning as dual mechanisms of action), has added materially to its value as a versatile therapeutic.
First immunotherapy for early stage triple-negative breast cancerDoriaFang
On July 27, Merck (MSD) announced that the FDA approved its blockbuster PD-1 antibody therapy Keytruda in combination with chemotherapy, as a neoadjuvant therapy before surgery, then continued as single agent as an adjuvant therapy after surgery, to treat high-risk early-stage triple-negative breast cancer (TNBC) patients.
SciTech Development LLC - Intelligent Technology to Solve Unmet Clinical Needs - Often the difference between success and failure is the dedication and persistence of the executive team. SciTech Development’s principal asset, fenretinide, is guided by a deeply experienced team in the broad portfolio of pharmaceutical development, clinical strategy, and scientific formulation.
a short presentation about the types of treatments used in cancer therapy, including traditional chemotherapy, targeted therapy, immunotherapy and hormonal therapy. also a short talk about side effects and administration of the CTX drugs.
Anti cancer peptide drug conjugates (pd cs) an overviewDoriaFang
Currently, ADC drug research has experienced a pile-up of targets, overlapping indication layouts and similar forms. There is an urgent need for a number of manufacturers to come up with new ideas to solve the existing problems. Some companies have taken an alternative route and laid out peptide-drug conjugate (PDC), which is relatively less competitive.
This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
A slide series to learn and appreciate the importance and the potential of Personalized/Individualized Genomic Medicine. It briefly goes through the idea of biotechnology and the advancements we have made in biology and technology. A series of applications for genomic medicine is then explored, not failing to mention the challenges we have to overcome as well, for the next medical revolution.
A case for personalized medicine is presented.
The maturation of genomic technologies has enabled new
discoveries in disease pathogenesis as well as new approaches to patient care.
In pediatric oncology, patients may now receive individualized genomic analysis to identify molecular aberrations of relevance for diagnosis and/or treatment.
Several recent clinical studies have begun to explore the feasibility and utility of genomics-driven precision medicine.
THERAPEUTIC POTENTIAL OF ANGIOGENESIS INHIBITOR MIXTURES IN CANCER TREATMENT,...ANCA MARIA CIMPEAN
ABSTRACT
It is generally understood that improvement of cancer therapies is achieved by the combination of drugs. This approach will improve efficacy, while toxicity and the risk for drug resistance may be decreased. In this review, the efforts on combining drugs for the treatment of two tumor types is highlighted, followed by a description of the challenges that are faced in designing optimal combination therapies.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
ST-001 NanoFenretinide - SciTech Development Lead Drug CompoundSciTech Development
SciTech’s lead compound, ST-001, is a small-molecule immune oncology (IO) nanoFenretinide cancer drug employed as an aqueous nanoparticle suspension for IV administration. The ST-001 nanoFenretinide drug is comprised of the active pharmaceutical ingredient (API) fenretinide in a patented combination with carefully selected phospholipids (inactive ingredients). ST-001 is designed to deliver a 15-fold higher drug to lipid ratio and a >6x concentration of the API than conventional IV formulations achieving therapeutically effective doses without the toxic side effects observed with other delivery systems – a benefit previously unattainable. Recent discovery of the API’s immunotherapeutic effect, in which a reactivated natural immune response compliments the previously understood safe, direct, chemotherapeutic effect (functioning as dual mechanisms of action), has added materially to its value as a versatile therapeutic.
First immunotherapy for early stage triple-negative breast cancerDoriaFang
On July 27, Merck (MSD) announced that the FDA approved its blockbuster PD-1 antibody therapy Keytruda in combination with chemotherapy, as a neoadjuvant therapy before surgery, then continued as single agent as an adjuvant therapy after surgery, to treat high-risk early-stage triple-negative breast cancer (TNBC) patients.
SciTech Development LLC - Intelligent Technology to Solve Unmet Clinical Needs - Often the difference between success and failure is the dedication and persistence of the executive team. SciTech Development’s principal asset, fenretinide, is guided by a deeply experienced team in the broad portfolio of pharmaceutical development, clinical strategy, and scientific formulation.
a short presentation about the types of treatments used in cancer therapy, including traditional chemotherapy, targeted therapy, immunotherapy and hormonal therapy. also a short talk about side effects and administration of the CTX drugs.
Anti cancer peptide drug conjugates (pd cs) an overviewDoriaFang
Currently, ADC drug research has experienced a pile-up of targets, overlapping indication layouts and similar forms. There is an urgent need for a number of manufacturers to come up with new ideas to solve the existing problems. Some companies have taken an alternative route and laid out peptide-drug conjugate (PDC), which is relatively less competitive.
This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
A slide series to learn and appreciate the importance and the potential of Personalized/Individualized Genomic Medicine. It briefly goes through the idea of biotechnology and the advancements we have made in biology and technology. A series of applications for genomic medicine is then explored, not failing to mention the challenges we have to overcome as well, for the next medical revolution.
A case for personalized medicine is presented.
Which Way Should be Chosen for Treatment of Metastatic Renal Cell Carcinoma?_...CrimsonpublishersCancer
There are two major pathways targeted for the treatment of metastatic renal cell cancer. One is VEGF inhibition that induces tumor shrinkage and increases progression-free survival and the other is Immune checkpoint inhibition that has been shown to increase overall survival. There are two clinically possible ways to block the antiangiogenic (VEGF) pathway. We can use Tyrosine kinase inhibitors (Sunitinib, Pazopanib, Cabozantinib, Axitinib, Sorafenib) that block the intracellular domain of the VEGFR or a monoclonal antibody (Bevacizumab) that binds to circulating VEGF and prevents it from activating VEGFR [1]. Checkpoint inhibition targeting the T lymphocyte-associated antigen 4 (CTLA-4) and/or programmed cell death receptor 1 (PD-1) pathway has led to significant improvements in the treatment of many malignancies, including renal cell carcinoma.
A normal cell can be transformed into a cancerous cell. Discuss the therapeutic strategies that are employed to target the cellular transformation process for cancer prevention and treatment.
Pathways and targets how might these affect my treatment decisions gail eckh...Fight Colorectal Cancer
Dr. Gail Eckhardt
Professor and Head of the Division of Medical Oncology at the University of Colorado Denver and Health Sciences Center.
Join us for an exciting webinar about pathways and targets. Dr. Eckhardt will discuss the basic of pathways within a cancer cell, and how (and why) they can affect treatment options for patients. She'll explain how we learn about how new pathways are discovered, and how this information tell us what drugs may work in certain patients and why some drugs don’t.
Dr. Eckhardt will discuss the idea of targeted therapies, and the difference between them and regular chemotherapy. She'll talk about the relationship between pathways and targeted drugs, and how this may impact drug development in the future.
HETEROGENEITY OF C ERB B FAMILY MEMBERS EXPRESSION IS RELATED TO CELL MORPHOL...ANCA MARIA CIMPEAN
ABSTRACT
Purpose. Epidermal growth factor receptor (EGFR, HER1) and human epidermal receptor 2 (HER2) assessement in pituitary adenomas related to hormone profile. Design and methods. For 60 retrospective cases of pituitary adenomas, we established the histopathologic diagnosis by using morphological stains, followed by case selection for immunoprofile and EGFR and HER 2 assessement. Results. More than one third of the studied pituitary adenomas (33,33%) were positive for HER2, with membranar pattern in basophilic cells and with predominantly cytoplasmic, granular pattern for acidophils cells. HER2 immuno-expression characterized PRL secreting adenomas (p=0.005) and associations between FSH-LH (p< 0.001) TSH-FSH (p=0,024) and TSH-LH (p=0.028). In situ hybridization confirmed HER2 gene amplification in 33,34% out of all positive cases for HER2 by immunohistochemistry. EGFR positivity was found significantly for GH-prolactin (p=0.000) and prolactin-ACTH (p=0.045) co-expressing pituitary adenomas, peritumoral macrophages and folliculostellate cells. Conclusions. Differential HER2 and EGFR expression related to hormone profile heterogeneity can define different subclasses of pituitary adenomas and could explain clinical, prognostic and therapeutic heterogeneity which are observed in clinical practice. Our results support re-classification of pituitary adenomas based on molecular approach which should include markers with well certified prognostic and therapeutic impact.
Key Words: HER2, EGFR,pituitary adenomas, targeted therapy
OVEREXPRESSION OF VEGF AND VEGFR2 IN CHRONIC HEPATITIS AND LIVER CIRRHOSISANCA MARIA CIMPEAN
VEGF (vascular endothelial growth factor) and the receptor for VEGF- Flk-1 (fetal liver kinase 1) are important players of normal and pathologic angiogenesis. Also, it was proved that they are involved in tumor progression and metastasis in many tumors types by overexpression in cancer cells. Liver malignances and premalignant lesions represent controversial issues concerning VEGF and VEGFR2 (vascular endothelial growth factor receptor 2) expression and their potential involvement in the progression of inflammatory and cirrhotic lesions and also in malignant transformation is virtually unknown. The aim of this work was to describe the differentiate expression and distribution of VEGF and VEGFR2 in chronic hepatitis and liver cirrhosis, and according to these findings to better characterize the molecular profiling of liver disease with malignant transformation potential. We investigated 20 cases with chronic hepatitis and cirrhosis on specimens taken during surgery. Immunohistochemistry was performed in all cases for VEGF, VEGFR2, and FVIII related antigen (Von Willebrand factor). We found significant correlation between HAI (histological activity index) value, VEGF and VEGFR2 expression and factor FVIII related antigen in central part of specimens with chronic hepatitis. Liver cirrhosis lacks this correlation. Our findings suggested that VEGF dependent angiogenesis is more active in chronic hepatitis in the center of the lesion compared with cirrhosis where MVD (microvessel density) is higher at the periphery of the nodules. We hypothesize that the involvement of VEGF and VEGFR2 complex in development of chronic hepatitis and liver cirrhosis could be considered for the use of anti VEGF antibodies as adjuvant therapy in early stages of these diseases.
Key Words: VEGF, VEGFR 2, liver cirrhosis, chronic hepatitis
EXPRESSION OF CK5 BASAL CYTOKERATIN DURING METASTATIC DEVELOPMENT OF BREAST C...ANCA MARIA CIMPEAN
Objective. Breast cancer is a one of the most common cancers in females worldwide. Basal cytokeratin CK5 represent the marker of progenitors for glandular and myoepithelial lineages of mammary epithelium. During epithelial differentiation there is a gradual decrease of CK5 expression. The purpose of this study was to compare the expression of basal cytokeratin CK5 vs hormone receptors, HER2, Ki67 and molecular subtypes immunohistochemically defined in the primary breast carcinoma of NST type and axillar lymph node metastasis. Material and Methods. We processed immunohistochemically 91 invasive breast carcinomas of NST type and their ipsilateral axillar lymph node metastasis (LNM). Results. The majority of primary tumors were evaluated as CK5 negative (78 cases/85.7%). The majority of cases were evaluated as Luminal B (50 cases/54.9%) and Luminal A (28 cases/30.8%) tumors. The HER2 subtype was confirmed in 8 cases/8.8%, 5NP in 3 cases/3.3% and Basal-like in 2 cases/2.2%. The parallel comparison of CK5 expression at both sites, primary and metastatic, revealed that this marker is not stable during metastatic progression. The molecular subtypes were not stable during metastatic process in 21 cases/23.1%. Conclusions. The majority of NST invasive ductal breast carcinomas are CK5 negative. The molecular subtypes and CK5 are not stable during metastatic process. Cancerous cells prefer to lose this marker in the lymph node environment. The presence of cases with simultaneous expression of CK5 and hormone receptors is an open field to debate the existence of other, transient molecular subtypes. We expect a further confirmation in larger study groups.
Key Words: molecular subtypes, invasive carcinoma NST type, basal cytokeratin.
WHO APPEARED FIRST IN OTOLARYNGOLOGY: CLINICIANS, ANATOMISTS OR HISTOLOGISTS?...ANCA MARIA CIMPEAN
HISTORICAL REVIEW
Otolaryngology is mainly associated with clinical practice. Despite of this actual evidence, otolaryngology can be considered, from historical point of view as a complex speciality made up of a mixture of several preclinical specialities as anatomy, histology, pathology and physiology. Several scientists who studied these specialities first, became then otolaryngologists and others were known in the medical literature because of their studies in other specialities than otolaryngology. Most of the historical papers were focused on the ear, other regions being neglected. This review presents the forgotten part of otolaryngology, especially its preclinical facts with importance in etiology and pathogenesis of various disease of the ear, nose and throat structures and thus, present work can be considered as a particular overview of „forgotten” otolaryngology.
Key words: otolaryngology, anatomy, histology, pathology
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
CDSCO and Phamacovigilance {Regulatory body in India}NEHA GUPTA
The Central Drugs Standard Control Organization (CDSCO) is India's national regulatory body for pharmaceuticals and medical devices. Operating under the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, the CDSCO is responsible for approving new drugs, conducting clinical trials, setting standards for drugs, controlling the quality of imported drugs, and coordinating the activities of State Drug Control Organizations by providing expert advice.
Pharmacovigilance, on the other hand, is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. The primary aim of pharmacovigilance is to ensure the safety and efficacy of medicines, thereby protecting public health.
In India, pharmacovigilance activities are monitored by the Pharmacovigilance Programme of India (PvPI), which works closely with CDSCO to collect, analyze, and act upon data regarding adverse drug reactions (ADRs). Together, they play a critical role in ensuring that the benefits of drugs outweigh their risks, maintaining high standards of patient safety, and promoting the rational use of medicines.
LIMITS OF ANTI-ANGIOGENIC THERAPY, Domenico Ribatti, Beatrice Nico
1. _____________________________
2 Research and Clinical Medicine, 2016, Vol. 1, Nr. 1
EDITORIAL
Angiogenesis is controlled by the balance between
molecules that have positive and negative regulatory
activities and this concept has led to the notion of
the angiogenic switch, which depends on an increased
production of one or more positive regulators of
angiogenesis [1]. Most human tumors arise and remain in
situ without angiogenesis for a long time before switching
to an angiogenic phenotype, through a pre-neoplastic
stage as occurs in breast and cervical carcinomas, which
becomes neovascularized before the malignant tumor
appears. Activation of the angiogenic switch has been
attributed to the synthesis or release of angiogenic
factors, and accordingly to the balance hypothesis, the
level of angiogenesis inducers and inhibitors regulates
angiogenesis in physiological conditions. This balance is
altered in pathological conditions, including tumors, as
a consequence of an increase bioavailability or activity
of the inducer proteins, or reducing the concentrations
of endogenous angiogenesis inhibitors. Restore of this
balance may induce a normalization of structure of
blood vessels. The concept of “normalization” of tumor
blood vessels by anti-angiogenic drugs was introduced
by Rakesh Jain in 2001 [2]. Accordingly, anti-vascular
endothelial growth factor (VEGF)/vascular endothelial
growth factor receptor (VEGFR) therapies induce
morpho-functional normalization of tumor blood
vessels, favoring an increase in blood flow and release of
cytotoxic drugs. However, in non small cell lung cancer
(NSCLC) anti-angiogenic therapy decreases cytotoxic
drug delivery to tumors [3]. The state of normalization
is probably transient and dependent on the dose and
duration of the treatment.
Beginning in the 1980’s, the industry exploited the
field of anti-angiogenesis for creating new therapeutic
molecules in angiogenesis-dependent diseases. However,
experimental drugs that in preclinical early stage
prevention or intervention trials have been proven
to efficiently impair the onset of tumor angiogenesis
may not exert any anti-angiogenic activity when tested
in late stage intervention or regression trials, as usually
performed in the clinics.
At present anti-angiogenic therapy is essentially
anti-VEGF)/VEGFR therapy and has yet fulfilled
its promise in the clinic. Bevacizumab (Avastin) was
the first angiogenesis inhibitor approved by the Food
and Drug Adminstration (FDA) for the treatment
of colorectal cancer in February 2004, administered
in combination with irinotecan, 5-fluorouracil and
leucovirin [4]. It was subsequently approved for use,
in combination with cytotoxic chemotherapy, in other
cancers. Actually, inhibition of VEGF/VEGFR axis
is obtained by targeting VEGF ligand with antibodies
or receptor traps, or its receptors with small-molecule
tyrosine kinase inhibitors (TKI). Clinical benefits are
obtained when ligand-blocking drugs are combined
with chemotherapeutic agents or radiotherapy, while
clinical studies testing various TKIs combined with
chemotherapy have failed becauseof increased cytoxicity.
Depending on cancer type, these anti-angiogenic
treatments can lead to a 3-6 months increase in
progression-free survival, but fail to provide enduring
clinical responses, with transitory improvements being
followed by a relapse phase in tumor angiogenesis and
subsequent tumor growth.
Removal of VEGF inhibition causes tumor re-
growth due to the fact that pericytes provide a scaffold
for the rapidly re-growing of tumor vessels [5]. The
occurrence of pericytes expressing alpha smooth muscle
actin (α-SMA) has been considered as a biomarker for
tumors refractory to therapy [6]. Pericytes have been
indicated as putative targets in the pharmacological
therapy of tumors by using the synergistic effect of
anti-endothelial and anti-pericytic molecules. Removal
of pericyte coverage leads to exposed tumor vessels,
which may explain the enhanced effect of combining
inhibitors that target both tumor vessels and pericytes.
Bergers et al. (2003) showed that combined treatment
or pre-treatment with anti-platelet derived growth factor
(PDGF-B)/platelet derived growth factor receptor beta
(PDGFBR-β) reducing pericyte coverage increases the
success of anti-VEGF treatment in the mouse RIP1-
TAG2 model [7]. PDGFR inhibition has been developed
LIMITS OF ANTI-ANGIOGENIC THERAPY
Domenico Ribatti*1,2
, Beatrice Nico1
1
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy,
2
National Cancer Institute “Giovanni Paolo II”, Bari, Italy
* Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11,
70124 Bari, Italy. E-mail: domenico.ribatti@uniba.it
2. _____________________________
D. Ribatti, B. Nico 3
in the context of combined inhibition of VEGFR and
PDGFR with dual-specificity small-molecule inhibitors,
including sunitinib, sorafenib, and pazopanib.
The results from clinical trials have not shown the
dramatic antitumor effects that were expected following
preclinical studies, which revealed a much higher efficacy
of these type of agent in animal models. Patients with
different types of tumors respond differently to anti-
angiogenic therapy. While colorectal, lung and breast
cancer patients have responded, pancreatic cancer
patients have not shown survival advantages when treated
with anti-angiogenic monotherapy or combinations of
anti-angiogenic agents with chemotherapy. Moreover,
responses to anti-angiogenic drugs vary between primary
tumors and their metastases [8].
Additionally, preclinical and clinical data have shown
the possibility that tumors may acquire resistance to anti-
angiogenic drugs or may escape anti-angiogenic therapy
via compensatory mechanisms. Most of the FDA-
approved drugs, as well as those in phase III clinical trials,
target a single pro-angiogenic protein. However, multiple
angiogenic molecules may be produced by tumors, and
tumors at different stages of development may depend
on different angiogenic factors for their blood supply.
Therefore, blocking a single angiogenic molecule might
have little or no impact on tumor growth. In 2011, it
has been introduced the use of dual fibroblast growth
factor receptor (FGFR)/VEGF TKI brivanib, that
inhibits VEGFR1-3 and disrupt FGFR1-3, overcoming
resistance to VEGF-selective therapy, and blocking FGF-
dependent tumor proliferation [9].
Finally, it has been demonstrated that angiogenesis
inhibitors make some tumors more aggressive in
different animals, increasing invasion and lymphatic or
hematogeneous metastasis [10,11].
REFERENCES
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