INTRODUCTION:

Cancer is a complex group of diseases characterized by the uncontrolled growth and spread of abnormal cells. These cells can form tumours or invade nearby tissues and organs, disrupting their normal functions. There are over 100 types of cancer, each with its unique characteristics, behaviour, and treatment strategies. Cancer can develop in any part of the body, and it often begins when genetic mutations accumulate within a cell, disrupting the regulatory mechanisms that control cell growth and division.

These mutations can “be caused” by various factors, including genetic predisposition, exposure to carcinogens (such as tobacco smoke, radiation, and certain chemicals), infections, and lifestyle choices. The hallmark of cancer is its ability to evade the body's natural mechanisms that regulate cell growth and prevent abnormal cell proliferation. Cancer cells can multiply uncontrollably and form a Mass of tissue known as a tumour. It’s important to note that not all tumours are cancerous. Benign tumours do not invade nearby tissues or spread to other "Parts of the body". On the other hand, malignant tumours are cancerous and can spread to other organs and tissues through the blood stream or lymphatic system. Prompt identification and progress in the study and management of cancer have enhanced the prognosis for several Cancer patients. Treatment options vary depending on the type and stage of cancer and may include surgery, chemotherapy, radiation therapy, immunotherapy, hormone therapy, targeted therapy, and stem cell transplantation. Despite significant progress, cancer remains a leading cause of morbidity and mortality worldwide. Ongoing research aims to uncover new insights into the "The Biology of Cancer". Develop more effective treatments, and improve early detection methods to enhance the overall management and prevention of this complex group of diseases.^1,2

TYPES:

Carcinomas are cancers that arise from epithelial cells, which are the cells that line the internal and external surfaces of the body. Common examples include lung cancer, breast cancer, prostate cancer, and colorectal cancer. Sarcomas are cancers that develop in connective tissues, such as bone, cartilage, fat, and muscle. Leukemias are cancers of the blood and bone marrow, involving abnormal production and proliferation of white blood cells. Lymphomas are cancers that originate in the lymphatic system, which is part of the body's immune system. Brain and spinal cord cancers, known as central nervous system cancers, can arise from various cell types within these organs. Melanoma is a type of skin cancer that develops from melanocytes, the pigment-producing cells in the skin. Additionally, there are cancers that can arise from other specialized cell types, such as germ cell tumors (originating from reproductive cells) and neuroendocrine tumors (arising from cells that produce hormones). Central Nervous System (CNS) cancers these cancers affect the brain and spinal cord. Gliomas, meningiomas, and medulloblastomas are examples of CNS cancers. Thyroid cancer this type of cancer develops in the thyroid gland, which produces hormones that regulate metabolism. Papillary and follicular carcinomas are common subtypes. Prostate cancer affecting the prostate gland in men, prostate cancer is one of the most common cancers in males. Ovarian cancer are those that originates in the ovaries, ovarian cancer is often diagnosed at an advanced stage due to its asymptomatic nature in the early stages. Pancreatic cancer which develops in the pancreas, this type of cancer is often diagnosed late and can be challenging to treat.²

Fig (1): Different types of cancer in different organs

OVERVIEW OF CARCINOGENESIS:

Carcinogenesis is the multi-step process by which normal cells are transformed into cancer cells. This process involves a series of genetic and epigenetic changes that lead to the uncontrolled proliferation of cells and their ability to invade and metastasize to other parts of the body. The process of carcinogenesis typically involves three main stages: initiation, promotion, and progression. Initiation occurs when a cell acquires genetic mutations or alterations that disrupt normal cellular processes, such as cell division, growth, and apoptosis (programmed cell death). These genetic changes can be caused by exposure to carcinogenic agents, such as radiation, chemicals, or viruses. During the promotion stage, the initiated cells undergo clonal expansion and acquire additional genetic and epigenetic changes that further enhance their proliferative and survival capabilities. This stage is often influenced by various factors, including hormones, inflammation, and exposure to tumor promoters. The progression stage is characterized by the accumulation of additional genetic and epigenetic alterations that confer more aggressive and invasive properties to the cancer cells. These changes may involve the activation of oncogenes, inactivation of tumor suppressor genes, and alterations in signaling pathways that regulate cell growth, angiogenesis (formation of new blood vessels), and metastasis.Throughout the carcinogenesis process, cancer cells acquire several hallmark capabilities, such as sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, induction of angiogenesis, and activation of invasion and metastasis. These capabilities enable cancer cells to overcome the normal regulatory mechanisms that govern cell growth and behavior, leading to the formation and progression of malignant tumors. It is important to note that carcinogenesis is a complex and multifactorial process, involving interactions between genetic and environmental factors, as well as the interplay between various cellular signaling pathways and the tumor microenvironment.³

Fig (2): Showing how the carcinogenesis process occurs in humans.

BREAST CANCER OVERVIEW:

Breast cancer is a type of cancer that begins in the cells of the breast. It can occur in both men and women, but it is far more common in women. The disease usually starts in the milk-producing glands (lobules), the ducts that transport milk to the nipple, or the supportive and connective tissue of the breast. In 2020, there were 2.3 million women diagnosed with breast cancer and 685,000 deaths globally. As of the end of 2020, there were 7.8 million women alive who were diagnosed with breast cancer in the past 5 years, making it the world's most prevalent cancer. Here's an explanation of breast cancer, covering risk factors, symptoms and types:

Risk Factors:

Women are at a higher risk of developing breast cancer, but men can also be affected. The risk increases with age, particularly after the age of 50. A family history of breast cancer and specific genetic mutations (e.g., BRCA1, BRCA2) can increase the risk. Previous cases of breast cancer or certain non-cancerous breast diseases can elevate the risk. Prolonged exposure to oestrogen, either through early menstruation, late menopause, or hormone replacement therapy, can be a risk factor. Late first pregnancy or never having children can contribute to an increased risk.

Symptoms:

A lump or thickening in the breast or underarm is a common symptom. Unexplained changes in the size or shape of the breast may occur. Skin changes such as redness, dimpling, or puckering may be signs of breast cancer. Changes in the nipple, such as inversion, discharge, or scaling, can be indicative. While not always present, breast cancer may cause pain or discomfort.⁴

Types of Breast Cancer:

There are several types of breast cancer, classified based on the origin and characteristics of the cancer cells. The most common types are invasive ductal carcinoma and invasive lobular carcinoma. Invasive ductal carcinoma begins in the milk ducts and can spread to surrounding breast tissue, while invasive lobular carcinoma originates in the lobules (milk-producing glands) and can also invade other areas. Other less common types include inflammatory breast cancer, which is an aggressive form that makes the breast appear swollen and red, and Paget's disease of the nipple, which starts in the nipple-areola complex. Additionally, breast cancer can be categorized as non-invasive or in situ, such as ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), which are confined to the ducts or lobules, respectively. Rare types of breast cancer include medullary, mucinous, and metaplastic carcinomas, which have distinct characteristics. The type of breast cancer, along with other factors like hormone receptor status and HER2 status, helps guide treatment decisions and prognosis.^5,6

ANATOMY OF BREAST

The breast is an intricate organ composed of several structures that work together to produce and secrete milk during lactation. At the center is the nipple, a protruding area surrounded by the pigmented areola. Underneath the areola are small glands called Montgomery glands that secrete lubricating fluids during breastfeeding. The bulk of the breast is made up of fatty connective tissue called adipose tissue, which gives the breast its soft and pliable texture. Interspersed within this fatty tissue are 15-20 lobes, each containing numerous tiny lobules, which are the milk-producing glands. These lobules are composed of tiny sacs called alveoli, where milk is synthesized and stored. A network of thin ducts connects the lobules to the nipple, providing a pathway for milk to flow out during breastfeeding. Supporting the breast structure are fibrous strands called Cooper's ligaments, which help maintain the breast's shape. The breast is also supplied by blood vessels that deliver oxygen and nutrients, as well as lymph vessels that drain excess fluid and waste products. While the breasts do not contain any muscle tissue, their size and shape can vary significantly due to factors like genetics, hormones, age, and body weight.^7-9

Fig. 3: Breast anatomy

FORMATION OF CANCER IN BREAST:

Breast cancer formation is a multi-step process that involves genetic and cellular changes over an extended period. It typically begins with a transformation in the breast cells' genetic material (DNA), causing mutations that disrupt normal cell growth and division. These initial mutations may be inherited or acquired through exposure to carcinogenic agents like radiation or chemicals. The transformed cells then undergo uncontrolled proliferation, forming a small cluster or lump called a primary tumor.¹⁰As the tumor grows, additional mutations accumulate, enabling the cancer cells to evade the body's immune defenses, resist cell death signals, and induce the formation of new blood vessels (angiogenesis) to sustain their growth. In some cases, cancer cells may break away from the primary tumor and enter the lymphatic system or bloodstream, a process known as metastasis. These circulating cancer cells can then travel to other parts of the body and establish new tumors, known as metastatic or secondary tumors, in organs like the lungs, liver, bones, or brain.¹¹ Throughout this process, the tumor microenvironment, including factors like inflammation, hormones, and the surrounding non-cancerous cells (stroma), can influence the growth and spread of breast cancer cells. The formation of breast cancer is a complex interplay between genetic alterations, cellular changes, and the tumor microenvironment, ultimately leading to the development of a malignant and potentially life-threatening condition.¹²

The different processes and elements that lead to breast cancer metastasis. Breast cancer metastasis is directly correlated with the induction of EMT. Additionally, by preserving and growing cancer stem cells with drug resistance and metastatic potential, a variety of cytokines released by TME and epigenetic modification facilitate the spread of breast cancer.

THERAPIES INVOLVED IN BREAST CANCER:

The treatment of breast cancer involves a multidisciplinary approach, often combining various therapies to effectively target and manage the disease. The choice of therapy depends on factors such as the type and stage of breast cancer, hormone receptor status, HER2/neu status, and the overall health of the individual. Several medicinal therapies play a vital role in the comprehensive management of breast cancer. Chemotherapy, which involves the use of cytotoxic drugs, is commonly employed to destroy rapidly dividing cancer cells. Regimens may include a combination of drugs like anthracyclines (e.g., doxorubicin), taxanes (e.g., paclitaxel), and cyclophosphamide.¹³ Targeted therapies, such as trastuzumab (Herceptin) and pertuzumab (Perjeta), are used for HER2-positive breast cancers to target and block the HER2 receptor, preventing cancer cell growth and proliferation. For hormone receptor-positive breast cancers, hormone therapies like tamoxifen (a selective estrogen receptor modulator) and aromatase inhibitors (e.g., letrozole, anastrozole) are prescribed to reduce estrogen levels or block estrogen receptors, depriving cancer cells of the hormones they need to grow. Newer targeted agents, such as CDK4/6 inhibitors (e.g., palbociclib, ribociclib), are used in combination with hormone therapy for advanced or metastatic hormone receptor-positive, HER2-negative breast cancers. Immunotherapies, like atezolizumab (Tecentriq) and pembrolizumab (Keytruda), which harness the body's immune system to recognize and attack cancer cells, are emerging as promising options, particularly for triple-negative and metastatic breast cancers.^14,15

Table 1: Some FDA-approved drugs used in breast cancer management.

S. No	Drugs	Mechanism	Ref.
1.	Abemaciclib	Abemaciclib inhibits the enzymes cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). These enzymes are responsible for phosphorylating and thus deactivating the retinoblastoma protein, which plays a role in cell cycle progression from the G1 (first gap) to the S (synthesis) phase. Blocking this pathway prevents cells from progressing to the S phase, thereby inducing apoptosis (cell death).	18
2.	Cyclophosph-amide	The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis	19
3.	Doxorubicin Hcl	Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being released and thereby stopping the process of replication. It may also increase quinone-type free radical production, hence contributing to its cytotoxicity.	20
4.	Anastrozole	Anastrozole is a medication primarily used in the treatment of breast cancer, especially in postmenopausal women with hormone receptor-positive breast cancer. It belongs to a class of drugs known as aromatase inhibitors. The mechanism of action of anastrozole is related to its ability to inhibit the enzyme aromatase. Aromatase is an enzyme responsible for the conversion of androgens (male hormones) into oestrogens (female hormones), particularly the conversion of testosterone to oestradiol. In postmenopausal women, the primary source of oestrogen is through this conversion in peripheral tissues, such as fat cells. By inhibiting aromatase, anastrozole reduces the production of oestrogen in the body.	21
5.	Tamoxifen	Tamoxifen is a medication that is commonly used in the treatment of hormone receptor-positive breast cancer. Its mechanism of action is primarily related to its ability to act as a selective oestrogen receptor modulator (SERM). Tamoxifen competes with oestrogen for binding to oestrogen receptors (ER) in the target tissues, particularly in the breast. Oestrogen is a hormone that can stimulate the growth of certain types of breast cancer cells. By binding to the oestrogen receptors on these cells, tamoxifen blocks the effects of oestrogen.	22
6.	Pertuzumab	Pertuzumab is a monoclonal antibody used in the treatment of HER2-positive breast cancer. It specifically targets the human epidermal growth factor receptor 2 (HER2 or ErbB2), a protein that is overexpressed in some breast cancers. Pertuzumab's mechanism of action involves inhibiting the dimerization (joining of two receptor molecules) of HER2 with other members of the HER family, such as HER3.	23
7.	Pembrolizumab	Pembrolizumab's mechanism of action involves targeting the programmed cell death protein 1 (PD-1) receptor on immune cells. Its primary role is to downregulate or inhibit the immune response, preventing excessive activation of the immune system and the development of autoimmune reactions. However, cancer cells can exploit the PD-1 pathway to evade the immune system.	24
8.	Ribociclib	Ribociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor used in the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. It works by inhibiting specific enzymes involved in cell cycle regulation.	[25]
9.	Methotrexate sodium	Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole carboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyl transferase. Inhibition of nucleotide synthesis prevents cell division.	[26]

Herbal therapies used in breast cancer.

Some herbs may also be used in cancer, including breast cancer, the use of herbs in cancer management should always be discussed with a healthcare professional. Herbs are not a substitute for conventional medical treatments, and their efficacy and safety can vary.Several herbs have been investigated for their potential role in breast cancer management, but more research is needed to establish their effectiveness. Some herbs that have been studied include:

1. Turmeric (Curcuma longa): Curcumin, the active compound in turmeric, has shown anti-cancer properties in laboratory studies. It may have potential benefits in preventing and treating breast cancer. It inhibits cell proliferation, cell cycle arrest at the G2/M phase, suppression of the FABP5/PPARβ/δ pathway, and inactivation of the Akt/mTOR pathway.²⁷

2. Green Tea (Camellia sinensis): Green tea contains polyphenols, particularly epigallocatechin gallate (EGCG), which has been studied for its anti-cancer properties. Some research suggests that green tea may help inhibit the growth of breast cancer cells.²⁸

3. Ginger (Zingiber officinale): Ginger has anti-inflammatory and antioxidant properties. Some studies have investigated its potential role in preventing and treating breast cancer, but more research is needed.

4. Flaxseed (Linum usitatissimum): Flaxseed is a source of lignans, which are compounds with antioxidant properties. Some studies have explored the potential of flaxseed in reducing the risk of breast cancer or slowing its progression.There was significant inhibition of cell proliferation and induced apoptosis via reduced mRNA expressions of cyclin D.²⁹

5. Echinacea: It is a herbal and medicinal plant belonging to the family Asteraceae. The extracts of Echinacea purpurea were found to promptly inhibit the growth of the BT-549 mammalian breast cancer cell line.³⁰

6. Astragalus (Astragalus membranous): This herb is commonly used in traditional Chinese medicine and has been studied for its immunomodulatory and anti-inflammatory effects. Some research has explored its potential role in supporting breast cancer patients, especially during chemotherapy.

7. Psidiumguajava: Several studies have investigated the anticancer activity of Psidiumguajava leaf extracts against different types of cancer, including breast cancer. One notable study published in the journal "Evidence-Based Complementary and Alternative Medicine" in 2012 examined the cytotoxic effects of guava leaf extracts on breast cancer cells. The researchers found that the extracts exhibited significant cytotoxic activity against breast cancer cell lines, inhibiting their growth and inducing apoptosis (programmed cell death).³¹

Table(2): Findings of researcher in breast cancer

S. No	Researcher/Year	Findings	Ref
1.	Neha et.al. /2023	Immunoliposomes represent a promising avenue in the realm of targeted drug delivery for breast cancer therapy. These nanocarriers are essentially liposomes - lipid-based vesicles - that are engineered to carry drugs or therapeutic agents specifically to cancer cells while sparing healthy tissues.	32
2.	Iris Garrido-Cano et.al., /2023	The delivery of miR-200c-3p using tumor-targeted mesoporous silica nanoparticles (MSNs) holds significant promise for breast cancer therapy. miR-200c-3p is a microRNA that plays a crucial role in regulating various cellular processes, including cell proliferation, migration, and invasion, which are often dysregulated in cancer.	33
3.	Reyhanehet, al., /2022	Curcumin, a bioactive compound found in turmeric, has gained considerable attention for its potential role in enhancing the therapeutic efficiency of chemotherapy drugs in breast cancer treatment. Several studies have investigated the synergistic effects of curcumin in combination with traditional chemotherapeutic agents, such as paclitaxel, doxorubicin, and cisplatin, aiming to improve treatment outcomes and reduce side effects.	34
4.	Yap et, al., /2021	The integration of nanocarriers with natural products holds great promise for the development of effective and safe therapeutic strategies for breast cancer treatment. This review provides valuable insights into the current landscape of research and identifies opportunities for further advancements in the field.	35
5.	Hernando et, al., /2021	Oral Selective Estrogen Receptor Degraders (SERDs) represent a promising frontier in breast cancer therapy, offering a novel approach with potential benefits from both efficacy and convenience standpoints.SERDs work by targeting the estrogen receptor (ER), which is commonly overexpressed in hormone receptor-positive breast cancers.	36
6.	Juan A et.al., /2020	Antibody-conjugated polymeric nanoparticles hold significant promise as a targeted therapy for breast cancer. Polymeric nanoparticles can be engineered to encapsulate therapeutic agents such as chemotherapy drugs or small interfering RNA (siRNA). By conjugating antibodies that specifically target antigens overexpressed on breast cancer cells, these nanoparticles can deliver their payload directly to the tumor site, minimizing systemic toxicity and enhancing efficacy.	37
7.	Tadahiko S et.al., /2020	Adjuvant and neoadjuvant therapies are vital components of breast cancer treatment, aimed at improving outcomes by reducing the risk of recurrence, shrinking tumors before surgery, or eradicating any remaining cancer cells post-surgery.	38
8.	Seock-Ah et.al., /2019	The MONALEESA-7 trial investigated the efficacy of ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, in combination with endocrine therapy compared to endocrine therapy alone in pre- and perimenopausal patients with hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer.	39
9.	Yin Hongran et, al., /2019	The delivery of anti-microRNA (anti-miRNA) therapies using RNA nanoparticles targeting the stem cell marker CD133 holds significant promise for triple-negative breast cancer (TNBC) therapy. CD133, also known as Prominin-1, is a cell surface marker associated with cancer stem cells (CSCs), a subpopulation of tumor cells implicated in tumor initiation, metastasis, and treatment resistance in TNBC. Targeting CD133-positive CSCs presents an attractive strategy for eradicating the most aggressive and therapy-resistant cells within the tumor.	40
10.	Namo P et, al., /2018	The treatment of advanced HER2-positive breast cancer has evolved significantly in recent years, offering patients a variety of effective therapeutic options. Trastuzumab, a monoclonal antibody targeting the HER2 receptor, Pertuzumab is another HER2-targeted monoclonal antibody that works synergistically with trastuzumab by inhibiting HER2 dimerization.	41
11.	J. Begam et, al., /2017	Estrogen receptor (ER) agonists and antagonists play crucial roles in breast cancer therapy, particularly in hormone receptor-positive (HR+) breast cancers. SERMs such as tamoxifen act as ER agonists in some tissues (e.g., bone and uterus) and as antagonists in others (e.g., breast tissue). Tamoxifen is a cornerstone of adjuvant therapy for HR+ breast cancer and has been shown to reduce recurrence and improve survival rates.	42
12.	Lili H et, al., /2016	Nanomedicine offers innovative strategies to specifically target breast cancer stem cells (BCSCs), a subpopulation of tumor cells implicated in tumor initiation, metastasis, and treatment resistance. Nanoparticles can be conjugated with ligands that specifically target surface markers overexpressed on BCSCs, such as CD44, CD133, and ALDH1. These ligands enhance nanoparticle binding to BCSCs, enabling targeted delivery of therapeutic payloads.	43
13.	Linda S et, al., /2016	Mammalian target of rapamycin (mTOR) inhibitors have emerged as promising therapeutic agents for the treatment of breast cancer, particularly in hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) subtypes. mTOR inhibitors, such as everolimus and temsirolimus, block mTOR activity, thereby inhibiting downstream signaling cascades involved in tumor cell proliferation and survival.	44
14.	Li Manhonget, al., /2015	The use of captopril-polyethyleneimine (PEI) conjugate-modified gold nanoparticles for co-delivery of drugs and genes holds significant promise in anti-angiogenesis breast cancer therapy. By targeting angiogenic pathways, such as the vascular endothelial growth factor (VEGF) pathway, anti-angiogenic agents can disrupt tumor blood supply and inhibit tumor progression.	45
15.	Zhao et, al., /2014	The utilization of fructose-coated nanoparticles as a drug nanocarrier holds promise for triple-negative breast cancer (TNBC) therapy. TNBC is characterized by high rates of glucose metabolism, known as the Warburg effect, which fuels tumor growth and aggressiveness. Targeting this metabolic vulnerability has emerged as a promising strategy for TNBC therapy.	46

Future Prospects of some therapies involved in breast cancer:

The prospects of breast cancer therapy are promising, with ongoing research and advancements aimed at improving treatment outcomes, minimizing side effects, and personalizing therapies based on individual characteristics. Here are some potential areas of development and innovation in breast cancer therapy, Immunotherapy, Targeted Therapies, Radiation Therapy, Chemotherapy, Nanotechnology, and Surgery.

Fig (6): Breast cancer therapies market in future.

CONCLUSION:

In conclusion, breast cancer and its therapies represent a dynamic and rapidly evolving field in the realm of oncology. Advances in understanding the molecular intricacies of the disease have paved the way for more personalized and targeted treatment approaches. Early detection remains paramount, emphasizing the importance of regular screenings and heightened awareness. The diversity of breast cancer subtypes necessitates a tailored and multidisciplinary approach to therapy, incorporating surgery, chemotherapy, radiation, hormone therapy, and targeted interventions. Ongoing research into immunotherapy and emerging targeted therapies holds promise for further improving treatment outcomes and minimizing side effects. Global collaboration and continued investment in research are essential for sustaining progress in the fight against breast cancer. Public awareness campaigns, early detection initiatives, and increased access to quality healthcare are crucial elements in reducing the burden of the disease worldwide. While significant strides have been made, breast cancer remains a formidable challenge. The journey from understanding the molecular basis of the disease to implementing effective, accessible, and patient-centred therapies is ongoing. With the combined efforts of researchers, healthcare professionals, advocates, and the global community, there is hope for further advancements that will ultimately contribute to improved outcomes and the eventual eradication of breast cancer as a major health threat.

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Received on 28.05.2024 Modified on 21.06.2024

Res. J. Pharmacology and Pharmacodynamics.2024;16(3):199-207.

DOI: 10.52711/2321-5836.2024.00034