Decreasing transmission and initiation of countrywide vaccination: Key challenges for future management of COVID-19 pandemic in Bangladesh.

With a fragile healthcare system, Bangladesh, much like other countries in South East Asia, struggled during the early days of COVID-19 pandemic. In following months several encouraging initiatives were undertaken including nationwide lockdown, maintaining social distancing and setting up COVID-19 dedicated laboratories and hospitals. Despite fear of an escalation in COVID-19 transmission during the winter months like their European counterparts, fortunately infection rates subsided and Bangladesh came out largely unharmed. But the next phase of COVID-19 pandemic management that includes viral transmission suppression and conduction of nationwide immunization program require several urgent steps from government of Bangladesh (GoB) and relevant stakeholders. This qualitative research piece discussed about issues including an urgent need to enhance critical care facilities around the country, especially in peripheral districts; ramping up COVID-19 testing at existing laboratories in view of diagnosing each case, and ensuring vaccines for the vulnerable populations in the country. Furthermore, the researchers shed light on other issues including a need to reinforce a struggling healthcare workforce, encouraging people to take vaccine, proper maintenance of social distancing regulations, routine epidemiological surveillance, management of environment and biomedical waste and undertaking a holistic approach to combat the pandemic and its environmental and financial consequences.

Pharmacological activation of PPAR-γ: a potential therapy for skin fibrosis.

Skin fibrosis caused by excessive collagen synthesis and deposition in the dermis affects the quality of daily life of hundreds of thousands of people around the world. The skin quality, including its smoothness in young age and wrinkly during the aging process, depends largely on the levels of extracellular matrix proteins such as collagen in skin. As physiological levels of collagen are desirable for skin homeostasis, beauty, and its flexibility, too much collagen deposition in the skin is associated with tight hard skin, loss of adipose layer, and flexibility, the pathological manifestations of skin fibrosis in fibrotic diseases such as scleroderma. To understand the molecular basis of skin fibrosis and in search of its therapy, different cellular, molecular, epigenetic, and preclinical studies have been undertaken to control abnormal excessive synthesis and accumulation of matrix protein collagen. Over the last two decades, numerous phase 1 through 3 clinical trials have been conducted to test the safety and efficacy of a wide variety of compounds in amelioration of skin fibrosis and other pathologies in scleroderma, yet, no effective therapy for skin fibrosis is available. This article solely focuses on the role of a nuclear receptor and transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR-γ), as an anti-skin fibrotic driving force and the potential therapeutic efficacies of PPAR-γ-specific ligands/agonists including antidiabetic drugs and other natural or semi-synthetic compounds derived from cannabis in amelioration of skin fibrosis in scleroderma. The underlying molecular basis of agonist-activated PPAR-γ-mediated suppression of profibrogenic signaling and skin fibrogenesis is also highlighted.

Stratification of patients with liver fibrosis using dual-energy CT.

Assessing the severity of liver fibrosis has direct clinical implications for patient diagnosis and treatment. Liver biopsy, typically considered the gold standard, has limited clinical utility due to its invasiveness. Therefore, several imaging-based techniques for staging liver fibrosis have emerged, such as magnetic resonance elastography (MRE) and ultrasound elastography (USE), but they face challenges that include limited availability, high cost, poor patient compliance, low repeatability, and inaccuracy. Computed tomography (CT) can address many of these limitations, but is still hampered by inaccuracy in the presence of confounding factors, such as liver fat. Dual-energy CT (DECT), with its ability to discriminate between different tissue types, may offer a viable alternative to these methods. By combining the "multi-material decomposition" (MMD) algorithm with a biologically driven hypothesis we developed a method for assessing liver fibrosis from DECT images. On a twelve-patient cohort the method produced quantitative maps showing the spatial distribution of liver fibrosis, as well as a fibrosis score for each patient with statistically significant correlation with the severity of fibrosis across a wide range of disease severities. A preliminary comparison of the proposed algorithm against MRE showed good agreement between the two methods. Finally, the application of the algorithm to longitudinal DECT scans of the cohort produced highly repeatable results. We conclude that our algorithm can successfully stratify patients with liver fibrosis and can serve to supplement and augment current clinical practice and the role of DECT imaging in staging liver fibrosis.

Proteasomal inhibition after injury prevents fibrosis by modulating TGF-ß(1) signalling.

BACKGROUND: The development of organ fibrosis after injury requires activation of transforming growth factor ß(1) which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-ß(1)-mediated transcription. METHODS: Bortezomib, a small molecule proteasome inhibitor in widespread clinical use, was administered to mice beginning 7 days after the intratracheal or intradermal administration of bleomycin and lung and skin fibrosis was measured after 21 or 40 days, respectively. To examine the mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis and scleroderma, respectively. RESULTS: Bortezomib promoted normal repair and prevented lung and skin fibrosis when administered beginning 7 days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from a patient with scleroderma, bortezomib inhibited TGF-ß(1)-mediated target gene expression by inhibiting transcription induced by activated Smads. An increase in the abundance and activity of the nuclear hormone receptor PPARγ, a repressor of Smad-mediated transcription, contributed to this response. CONCLUSIONS: Proteasomal inhibition prevents lung and skin fibrosis after injury in part by increasing the abundance and activity of PPARγ. Proteasomal inhibition may offer a novel therapeutic alternative in patients with dysregulated tissue repair and fibrosis.

Phase I trial of daily oral Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia.

PURPOSE: To define the optimal dose of Polyphenon E for chronic daily administration and tolerability in patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Previously untreated patients with asymptomatic Rai stage 0 to II CLL were eligible for participation. Polyphenon E with a standardized dose of epigallocatechin-3-gallate (EGCG) was administered using the standard phase I design with three to six patients per dose level (range, 400 to 2,000 mg by mouth twice a day). Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the National Cancer Institute (NCI) Working Group (WG) Criteria. RESULTS: Thirty-three eligible patients were accrued to dose levels 1 to 8. The maximum-tolerated dose was not reached. The most common adverse effects included transaminitis (33%, all grade 1), abdominal pain (30% grade 1, 0% grade 2, and 3% grade 3), and nausea (39% grade 1 and 9% grade 2). One patient experienced an NCI WG partial remission. Other signs of clinical activity were also observed, with 11 patients (33%) having a sustained > or = 20% reduction in absolute lymphocyte count (ALC) and 11 (92%) of 12 patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.9 to 3,974 ng/mL (median, 40.4 ng/mL). CONCLUSION: Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. A phase II trial to evaluate efficacy using 2,000 mg twice a day began in November 2007.

Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG.

PURPOSE: Chronic lymphocytic leukemia (CLL) is incurable with current chemotherapy treatments. Curcumin (diferuloylmethane), an active ingredient in the spice turmeric, inhibits tumor metastasis, invasion, and angiogenesis in tumor cell lines. We evaluated the effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection. EXPERIMENTAL DESIGN: The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated. RESULTS: Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 micromol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor kappaB. Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection. CONCLUSIONS: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted.

Black tea (Camellia sinensis) as a chemopreventive agent in oral precancerous lesions.

Oral carcinoma is the most common malignancy found in adult Indian men and the third most common in adult Indian women. About half of all cases are found to be associated with precancerous lesions, chiefly leukoplakia. We wanted to explore the possible benefits of black tea (Camellia sinensis) administered to patients with oral leukoplakia. Eighty-two subjects with oral leukoplakia underwent micronuclei and chromosomal assays on exfoliated oral mucosal epithelium, after which they received black tea in a fixed regimen. The micronuclei assay was repeated at 6 months, and the chromosomal study at 1 year. After the first year, the first 15 patients entered onto this study showed a significant decrease in the micronuclei frequency and chromosomal aberrations, which correlated with the clinical improvement. Several in vitro and animal studies have suggested the efficacy of tea in the chemoprevention of cancer. To the best of our knowledge, this is the first report on the effect of black tea in oral leukoplakia.